Preparation method of 5-bromoacetyl salicylamide
By adding acetonitrile in the synthesis process of 5-bromoacetylsalicylamide and using diethyl phosphite for post-treatment, the problems of high impurity content, low purity and low yield in the prior art are solved, and high yield and high purity product preparation is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202311456420.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-03
- Publication Date
- 2025-05-06
AI Technical Summary
In the existing synthesis methods of 5-bromoacetylsalicylamide, the impurity content in the product is relatively high, the product purity is not high, and the yield is relatively low, resulting in low raw material utilization, which is not conducive to industrial production.
Acetonitrile was added during the reaction and diethyl phosphite was used for post-treatment in the presence of triethylamine to reduce the generation of impurities and improve the reaction yield, and obtain high yield and high purity products.
By reducing the generation of impurities, the reaction yield is improved, and the obtained product has high yield and high purity, which is suitable for industrial production.
Smart Images
Figure CN119930459A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, in particular to a preparation method of 5-bromoacetyl salicylic acid amide. Background Art
[0002] 5-Bromoacetylsalicylicylamide is an important intermediate for the synthesis of labetalol hydrochloride, and its molecular structure is as follows:
[0003] There are many ways to synthesize 5-bromoacetyl salicylamide. The main synthesis method at present is to react 5-acetylsalicylicamide (5ASA) with bromine, and then centrifuge to obtain the product. For example, the document: Preparation of 5-bromoacetyl salicylamide, Xu Juanjuan et al., Fine Chemical Intermediates 36.2 (2006): 2 discloses a method for preparing 5-bromoacetyl salicylamide by brominating 5-acetylsalicylicamide with Br2.
[0004] However, the products obtained by the above methods in the prior art usually contain more impurities such as raw materials and dibromo substituents, and the product yield is low, generally only about 80%. The main impurity molecular structure is:
[0005] Therefore, in order to obtain a product with a qualified impurity content, it is necessary to control the content of the dibromo substituent, and the feed ratio of bromine and acetylsalicylic acid amide has to be reduced during the reaction, resulting in a low raw material utilization rate, which is not conducive to actual production. Summary of the invention
[0006] The invention aims to overcome the problems of high impurity content in products, low product purity and low yield in the synthesis method of 5-bromoacetyl salicylamide in the prior art, and provides a preparation method of 5-bromoacetyl salicylamide. Acetonitrile is added during the reaction, and the product is post-treated with diethyl phosphite in the presence of triethylamine, so that the generation of impurities can be effectively reduced, the reaction yield is improved, and a product with high yield and high purity can be obtained, which is suitable for industrial production.
[0007] In order to achieve the above object, the present invention adopts the following technical solutions: A method for preparing 5-bromoacetyl salicylamide comprises the following steps: (1) mixing 5-acetylsalicylicylamide, methanol and acetonitrile, and performing a heat-insulating reaction to obtain a mixed material; (2) adding a bromine acetonitrile solution dropwise to the mixed material, heating and refluxing the mixture; after stopping the reaction, evacuating the material in the system until the evaporated material is colorless; (3) adding methanol and triethylamine to the material after cooling to room temperature, adding diethyl phosphite after stirring, and heating to reflux for reaction; after the reaction is completed, cooling, centrifuging, and drying to obtain the 5-bromoacetyl salicylamide.
[0008] The present invention uses Br2 to brominate 5-acetylsalicylic acid amide to prepare 5-bromoacetylsalicylic acid amide, and adopts the method of adding acetonitrile to form a hydrogen bond between the phenolic hydroxyl group of 5-acetylsalicylic acid amide and acetonitrile, which reduces the activity on the benzene ring on the one hand, and increases the steric hindrance of the ortho position of the phenolic hydroxyl group on the other hand, so that the bromine (impurity A) on the impurity ring is difficult to generate during the reaction. For the dibromo compound (impurity B) generated on the acetyl group, the present invention uses a small amount of diethyl phosphite in the presence of triethylamine in the post-processing process to take off a bromine, so that it is converted into the target product 5-bromoacetylsalicylic acid amide again. Therefore, the present invention can make 5-acetylsalicylic acid amide fully react, greatly reduce the generation of impurities, improve the reaction yield, and can obtain a high-yield and high-purity product, which is suitable for industrial production.
[0009] Preferably, the mass ratio of 5-acetylsalicylicylamide, methanol and acetonitrile added in step (1) is 1:3.5-5:0.5-1. When the amount of acetonitrile added is within this range, the brominated impurities on the benzene ring can be completely controlled.
[0010] Preferably, the temperature of the insulation reaction in step (1) is 35 to 45° C., and the insulation reaction time is 25 to 35 min.
[0011] Preferably, the molar ratio of bromine to 5-acetylsalicylicylamide added in step (2) is 1.0-1.1:1.
[0012] Preferably, in the acetonitrile solution of bromine in step (2), the mass ratio of bromine to acetonitrile is 1:1-2.5, and the dropping time of the acetonitrile solution of bromine is controlled to be 15-20 hours.
[0013] Preferably, the reflux reaction temperature in step (2) is 63-65° C., and the reflux reaction time is 1-2 h.
[0014] Preferably, after the reflux reaction in step (2), sampling is performed for mid-control, and if the remaining amount of the raw material 5-acetylsalicylicylamide is less than 2%, the reaction is stopped.
[0015] Preferably, in step (3), the amount of triethylamine added is 0.1 to 0.3 equivalents of 5-bromoacetyl salicylamide; and the amount of diethyl phosphite added is 0.05 to 0.15 equivalents of 5-bromoacetyl salicylamide.
[0016] Preferably, the reflux reaction temperature in step (3) is 60-68° C., and the reflux reaction time is 1.5-2.5 h.
[0017] Preferably, after the reflux reaction in step (3) is completed, the temperature is lowered to 0-5°C to allow the product to precipitate in the form of a solid in the largest amount, and stirring is continued for 0.5-1.5h, followed by centrifugation.
[0018] Therefore, the present invention has the following beneficial effects: (1) Adding acetonitrile during the reaction can reduce the generation of brominated impurities (impurity A) during the reaction; (2) In the post-treatment process, a small amount of diethyl phosphite is used in the presence of triethylamine to remove one bromine in the dibromo compound (impurity B), so that it is converted back into the target product 5-bromoacetylsalicylicylamide, thereby allowing 5-acetylsalicylicylamide to fully react, thereby improving the reaction yield and being able to obtain a high-yield and high-purity product. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 It is the liquid chromatogram of the product obtained in Example 1 of the present invention.
[0020] Figure 2 It is the liquid chromatogram of the product obtained in Comparative Example 1 of the present invention.
[0021] Figure 3 It is the liquid chromatogram of the product obtained in Comparative Example 2 of the present invention. DETAILED DESCRIPTION
[0022] The present invention is further described below in conjunction with specific implementation methods.
[0023] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments, unless otherwise specified, are conventional methods in the art.
[0024] Overall embodiment: A method for preparing 5-bromoacetyl salicylamide comprises the following steps: (1) 5-acetylsalicylicylamide, methanol and acetonitrile are mixed at a mass ratio of 1:3.5-5:0.5-1 at room temperature, and the mixture is heated to 35-45° C. and kept for reaction for 25-35 minutes to obtain a mixed material; (2) dissolving bromine in acetonitrile to obtain an acetonitrile solution of bromine, wherein the mass ratio of bromine to acetonitrile is 1:1 to 2.5; dropping the acetonitrile solution of bromine into the mixed material, wherein the molar ratio of the added bromine to 5-acetylsalicylic acid amide is 1.0 to 1.1:1, and the dropping time is controlled within 15 to 20 hours; heating to 63 to 65° C. and reflux reaction for 1 to 2 hours; sampling and controlling the residual 5-acetylsalicylic acid amide of the raw material to be less than 2%, stopping the reaction; and then evacuating the material in the system until the evaporated material is colorless; (3) After the temperature is cooled to room temperature, methanol is added to the material to dissolve the material, and triethylamine is added, and diethyl phosphite is added after stirring; the amount of triethylamine added is 0.1 to 0.3 equivalents of 5-bromoacetyl salicylic acid amide; the amount of diethyl phosphite added is 0.05 to 0.15 equivalents of 5-bromoacetyl salicylic acid amide; the temperature is raised to 65 to 68° C. and refluxed for reaction for 1.5 to 2.5 hours; after the reaction is completed, the temperature is lowered to 0 to 5° C., stirring is continued for 0.5 to 1.5 hours, and the 5-bromoacetyl salicylic acid amide is obtained after centrifugation and drying.
[0025] Embodiment 1: A method for preparing 5-bromoacetyl salicylamide comprises the following steps: (1) 89.6 g of 5-acetylsalicylicylamide, 360 g of methanol and 80 g of acetonitrile were added to a reaction flask, the temperature was raised to 40° C., and stirred for 30 minutes to obtain a mixed material; (2) dissolving 84 g of bromine in 170 g of acetonitrile to obtain an acetonitrile solution of bromine; slowly adding all of the acetonitrile solution of bromine to the mixed material dropwise, with the dropping time controlled within 15 h; (3) After the addition is complete, heat to 65°C and reflux for 1 h; (4) Sampling control, 5-acetylsalicylic acid amide remaining 1.37%, stop the reaction; (5) Evacuate the system, open the condenser, and stop when the color of the distilled material becomes colorless and transparent; (6) Cooling to room temperature, adding 10 g of triethylamine and 78 g of methanol to the reaction flask, and stirring; (7) Add 6.9 g of diethyl phosphite to the reaction flask, heat to 65° C. and reflux for 2 h; (8) Cool the material to 5°C and continue stirring for 1 hour; (9) Centrifuge and dry the material to obtain 116.7 g of product with a yield of 90.4% and a purity of more than 98%. The product was analyzed by liquid chromatography. The results are as follows Figure 1 as shown in .
[0026] Embodiment 2: A method for preparing 5-bromoacetyl salicylamide comprises the following steps: (1) 89.6 g of 5-acetylsalicylicylamide, 440 g of methanol and 80 g of acetonitrile were added to a reaction flask, the temperature was raised to 40° C., and stirred for 30 minutes to obtain a mixed material; (2) dissolving 88 g of bromine in 170 g of acetonitrile to obtain an acetonitrile solution of bromine; slowly adding all of the acetonitrile solution of bromine to the mixed material dropwise, with the dropping time controlled within 17 h; (3) After the addition is complete, heat to 65°C and reflux for 1 h; (4) Sampling control: 5-acetylsalicylic acid amide remained at 1.13%, and the reaction was stopped; (5) Evacuate the system, open the condenser, and stop when the color of the distilled material becomes colorless and transparent; (6) Cooling to room temperature, adding 15 g of triethylamine and 53 g of methanol to the reaction flask, and stirring; (7) Add 6.9 g of diethyl phosphite to the reaction flask, heat to 65° C. and reflux for 2 h; (8) Cool the material to 5°C and continue stirring for 1 hour; (9) Centrifuge and dry the material to obtain 120.4 g of product with a yield of 93.3% and a purity of more than 98%.
[0027] Embodiment 3: A method for preparing 5-bromoacetyl salicylamide comprises the following steps: (1) 89.6 g of 5-acetylsalicylicylamide, 400 g of methanol and 60 g of acetonitrile were added to a reaction flask, the temperature was raised to 40° C., and stirred for 30 minutes to obtain a mixed material; (2) dissolving 88 g of bromine in 140 g of acetonitrile to obtain an acetonitrile solution of bromine; slowly adding all of the acetonitrile solution of bromine to the mixed material dropwise, with the dropping time controlled within 15 h; (3) After the addition is complete, heat to 65°C and reflux for 1 h; (4) Sampling control, 5-acetylsalicylic acid amide remaining 1.89%, stop the reaction; (5) Evacuate the system, open the condenser, and stop when the color of the distilled material becomes colorless and transparent; (6) Cooling to room temperature, adding 10 g of triethylamine and 66 g of methanol to the reaction flask, and stirring; (7) Add 10 g of diethyl phosphite to the reaction flask, heat to 65° C. and reflux for 2 h; (8) Cool the material to 5°C and continue stirring for 1 hour; (9) Centrifuge and dry the material to obtain 118.0 g of product with a yield of 91.4% and a purity of more than 98%.
[0028] Comparative Example 1 (without addition of acetonitrile): A method for preparing 5-bromoacetyl salicylamide comprises the following steps: (1) 89.6 g of 5-acetylsalicylicylamide and 360 g of methanol were added to a reaction flask, the temperature was raised to 40° C., and stirred for 30 minutes to obtain a mixed material; (2) Dissolve 84 g of bromine in 170 g of methanol to obtain a methanol solution of bromine; slowly dropwise add all of the methanol solution of bromine to the mixed material, and the dropping time is controlled within 15 hours; (3) After the addition is complete, heat to 65°C and reflux for 1 h; (4) Sampling control, 5-acetylsalicylic acid amide remaining 1.42%, stop the reaction; (5) Evacuate the system, open the condenser, and stop when the color of the distilled material becomes colorless and transparent; (6) Cooling to room temperature, adding 10 g of triethylamine and 87 g of methanol to the reaction flask, and stirring; (7) Add 6.9 g of diethyl phosphite to the reaction flask, heat to 65° C. and reflux for 2 h; (8) Cool the material to 5°C and continue stirring for 1 hour; (9) Centrifuge and dry the material to obtain 112.3 g of product with a yield of 87% and a purity of 97.01%. The product was analyzed by liquid chromatography. The results are as follows Figure 2 as shown in .
[0029] Comparative Example 2 (post-treatment without diethyl phosphite and triethylamine): A method for preparing 5-bromoacetyl salicylamide comprises the following steps: (1) 89.6 g of 5-acetylsalicylicylamide, 360 g of methanol and 80 g of acetonitrile were added to a reaction flask, the temperature was raised to 40° C., and stirred for 30 minutes to obtain a mixed material; (2) dissolving 84 g of bromine in 170 g of acetonitrile to obtain an acetonitrile solution of bromine; slowly adding all of the acetonitrile solution of bromine to the mixed material dropwise, with the dropping time controlled within 15 h; (3) After the addition is complete, heat to 65°C and reflux for 1 h; (4) Sampling control, 5-acetylsalicylic acid amide remaining 1.37%, stop the reaction; (5) Evacuate the system, open the condenser, and stop when the color of the distilled material becomes colorless and transparent; (6) Cool down to 5°C and continue stirring for 1 h; (7) Centrifuge and dry the material to obtain 110.2 g of product with a yield of 85% and a purity of 96.26%. The product was analyzed by liquid chromatography. The results are as follows Figure 3 as shown in .
[0030] From the results of the above embodiments and comparative examples and Figure 1 It can be seen that the products obtained by the method of the present invention in Examples 1 to 3 have high yield and purity and low impurity content.
[0031] And as Figure 2 As shown in , in Comparative Example 1, acetonitrile is not added during the preparation process, which will produce more impurity A, resulting in a significant decrease in the yield and purity of the product compared with those in the examples.
[0032] like Figure 3 As shown in , in Comparative Example 2, the product was not post-treated with diethyl phosphite, the content of impurity B in the product was relatively high, and the yield and purity of the product were also reduced.
[0033] Therefore, by adopting the method of the present invention, 5-acetylsalicylicylamide can be fully reacted, the generation of impurities is greatly reduced, the reaction yield is improved, and a high-yield and high-purity product can be obtained, which is suitable for industrial production.
Claims
1. A method for preparing 5-bromoacetyl salicylamide, characterized in that: The steps include: (1) 5-acetylsalicylicylamide, methanol and acetonitrile are mixed and reacted at a temperature keeping warm to obtain a mixed material; (2) Add the acetonitrile solution of bromine dropwise to the mixed material, raise the temperature and reflux for reaction; after stopping the reaction, evacuate the material in the system until the evaporated material is colorless; (3) After the temperature drops to room temperature, methanol and triethylamine are added to the material, and diethyl phosphite is added after stirring, and the temperature is raised to reflux for reaction; after the reaction is completed, the temperature is lowered, centrifuged, and dried to obtain the 5-bromoacetyl salicylamide.
2. The preparation method according to claim 1, characterized in that: The mass ratio of 5-acetylsalicylicylamide, methanol and acetonitrile added in step (1) is 1:3.5~5:0.5~1.
3. The preparation method according to claim 1 or 2, characterized in that: The temperature of the insulation reaction in step (1) is 35-45° C., and the insulation reaction time is 25-35 min.
4. The preparation method according to claim 1, characterized in that: The molar ratio of bromine to 5-acetylsalicylicylamide added in step (2) is 1.0-1.1:
1.
5. The preparation method according to claim 1 or 4, characterized in that: In the acetonitrile solution of bromine in step (2), the mass ratio of bromine to acetonitrile is 1:1-2.5, and the dropping time of the acetonitrile solution of bromine is controlled to be 15-20 hours.
6. The preparation method according to claim 1, characterized in that: In step (2), the reflux reaction temperature is 63-65° C., and the reflux reaction time is 1-2 h.
7. The preparation method according to claim 1 or 6, characterized in that: After the reflux reaction in step (2), sampling is performed for mid-control. If the remaining amount of the raw material 5-acetylsalicylicylamide is less than 2 wt %, the reaction is stopped.
8. The preparation method according to claim 1, characterized in that: In step (3), the amount of triethylamine added is 0.1 to 0.3 equivalents of 5-bromoacetyl salicylamide; the amount of diethyl phosphite added is 0.05 to 0.15 equivalents of 5-bromoacetyl salicylamide.
9. The preparation method according to claim 1 or 8, characterized in that: In step (3), the reflux reaction temperature is 60-68° C., and the reflux reaction time is 1.5-2.5 h.
10. The preparation method according to claim 1 or 8, characterized in that: After the reflux reaction in step (3) is completed, the temperature is lowered to 0-5°C, stirring is continued for 0.5-1.5h, and then centrifugation is performed.