Preparation method of 3-bromo-4-fluorobenzaldehyde

Abstract

The invention discloses a preparation method of 3-bromine-4-fluorobenzaldehyde based on continuous flow reaction, which comprises the following step: carrying out bromination reaction on dibromohydantoin, a sulfuric acid aqueous solution and p-fluorobenzaldehyde under the catalysis of benzyltriethylammonium chloride. According to the invention, dibromohydantoin with low toxicity is used as a brominating agent, a cosolvent benzyltriethylammonium chloride is added during reaction, then sulfuric acid water is directly used as a solvent, the use of an organic solvent is avoided, and finally, the residual raw material p-fluorobenzaldehyde is removed under reduced pressure by using an azeotropic method, so that disproportionation side reaction during high-temperature distillation and purification of the product is avoided, and the yield of the product is improved. The purity of the product is ensured, meanwhile, the crystallization loss of the product during the body melt crystallization purification is also avoided, and the yield of the product is ensured; besides, the preparation method of continuous flow reaction is adopted, compared with an intermittent tank reactor, the continuous flow reaction has higher production efficiency and reaction safety, and industrial production of the product is easier to realize.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to a method for preparing 3-bromo-4-fluorobenzaldehyde, a key intermediate of Olaparib, a drug for treating breast cancer. Background Art

[0002] Olaparib is a targeted therapy drug mainly used to treat advanced ovarian cancer, breast cancer and other types of cancer with BRCA gene mutations. It is a PARP inhibitor that inhibits the growth and reproduction of cancer cells by blocking the ability of cancer cells to repair their own DNA. It is currently available in Europe, America, China, India, Japan and South America.

[0003] The preparation method of 3-bromo-4-fluorobenzaldehyde disclosed in Chinese patent publication number CN1255481A is to react p-fluorobenzaldehyde with NBS in anhydrous ether or concentrated sulfuric acid at 0-20°C, filter, evaporate ether, perform high vacuum distillation, and collect 110-112°C fractions. This method uses NBS as a brominating agent, the reaction conversion yield is not high, and when the product is finally distilled at high vacuum and high temperature, the aldehyde group will undergo a disproportionation side reaction, resulting in a yield of only 80% and a product content of only 98%. In particular, during industrial production, the high-temperature distillation time will be extended several times, the disproportionation side reaction of the aldehyde group will increase exponentially, and the product quality and yield will be significantly reduced, so this preparation method is not suitable for industrial production.

[0004] The preparation method of 3-bromo-4-fluorobenzaldehyde disclosed in Chinese patent publication number CN1508124A is to react p-fluorobenzaldehyde in dichloroethane with anhydrous aluminum chloride as a catalyst, add bromine and chlorine gas, and after the reaction is completed, wash the reaction materials with water and acid, separate the oil layer, and evaporate the dichloroethane to obtain a reddish brown oil with a content of 92% and a yield of 90%. This method uses bromine and chlorine gas with relatively high toxicity, which is not friendly to the environment and has great safety hazards in industrial production. In addition, this method avoids the disproportionation side reaction during high-temperature distillation, but the p-fluorobenzaldehyde that has not reacted completely remains in the product, resulting in a product content of only 92%, which is not suitable for use as a pharmaceutical intermediate.

[0005] The preparation method of 3-bromo-4-fluorobenzaldehyde disclosed in Chinese patent publication number CN1109912396B is to dissolve p-fluorobenzaldehyde in dichloromethane, use sodium bromide and hydrochloric acid, sodium hypochlorite as brominating agents, complete the bromination reaction under ultrasonic catalysis, and purify the product by bulk melt crystallization, the purity reaches 99.2%, and the yield is about 90%; the ultrasonic catalysis scheme of this method will be limited by equipment when industrialized, and the product is purified by bulk melt crystallization, the product yield is usually not high, so this preparation method is not suitable for industrial production.

[0006] The above three preparation schemes have the disadvantages of unsatisfactory purification and refining schemes, poor product quality, or low product yield. In addition, the traditional intermittent production efficiency is low, which is also an area that urgently needs to be improved. Summary of the invention

[0007] In view of the shortcomings of the prior art, the present invention provides a method for preparing 3-bromo-4-fluorobenzaldehyde based on a continuous flow reaction. Compared with an intermittent kettle reactor, the continuous flow reaction has higher production efficiency and reaction safety, and the product is easier to realize industrial production.

[0008] To achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0009] The invention discloses a method for preparing 3-bromo-4-fluorobenzaldehyde. The method adopts a continuous flow reaction, uses p-fluorobenzaldehyde as a raw material, uses dibromohexane as a brominating agent, uses a sulfuric acid aqueous solution as a reaction solvent, and uses benzyltriethylammonium chloride as a co-solvent to carry out a bromination reaction. After the reaction is completed, the obtained reaction slurry is post-processed and purified in an intermittent reactor.

[0010] More specifically, a method for preparing 3-bromo-4-fluorobenzaldehyde, using a continuous flow reaction, comprises the following steps:

[0011] (1) Add dibromohydantoin (Formula III), benzyltriethylammonium chloride, sulfuric acid aqueous solution, and p-fluorobenzaldehyde (Formula II) into a raw material tank and stir evenly;

[0012] (2) pumping the slurry in the raw material tank into the preheating zone of the tubular reactor through a metering pump for preheating;

[0013] (3) passing the preheated slurry into a tubular reactor for reaction to obtain a crude product of 3-bromo-4-fluorobenzaldehyde (Formula I);

[0014]

[0015] Furthermore, the method further comprises post-processing and purifying the crude product slurry obtained from the continuous flow reaction in an intermittent reactor to obtain a product, wherein the post-processing and purification comprises the following steps:

[0016] (1) Adding sodium sulfite to the slurry after the reaction is completed, stirring, allowing the slurry to stand for stratification, and discarding the aqueous layer;

[0017] (2) Add water and sodium carbonate to the organic layer, stir, separate the layers, and discard the aqueous layer.

[0018] (3) Add water to the oil layer, distill under reduced pressure at 55-60°C with stirring, azeotropically distill off water and p-fluorobenzaldehyde, and collect the residue to obtain the product 3-bromo-4-fluoroformaldehyde.

[0019] Preferably, the mass concentration of the aqueous sulfuric acid solution is 20%-40%.

[0020] Preferably, the mass ratio of dibromohydantoin, benzyltriethylammonium chloride, 20%-40% sulfuric acid aqueous solution and p-fluorobenzaldehyde is 1650-2000:50:4000:1240.

[0021] Preferably, the preheating temperature in step (2) is 120-125°C, and the reaction time is 12-15 minutes; after the reaction in the tubular reactor in step (3) is complete, the slurry is passed into a product collection tank and cooled to 30-35°C.

[0022] Preferably, the crude product slurry obtained by the continuous flow reaction is post-treated and purified in a batch reactor to obtain a product, and the post-treatment purification comprises the following steps:

[0023] (1) Add 0.1% sodium sulfite by weight of the slurry to the slurry after the reaction is completed, stir for 0.5 hour, let it stand and separate into layers, and discard the water layer;

[0024] (2) Add 10% of the slurry weight of water and 2.0% of the slurry weight of sodium carbonate to the organic layer, stir, separate the layers, and discard the aqueous layer.

[0025] (3) Add 5.0% of the weight of the slurry water to the oil layer, distill under reduced pressure at 55-60°C with stirring, azeotropically distill off water and p-fluorobenzaldehyde, and collect the residue to obtain the product 3-bromo-4-fluoroformaldehyde.

[0026] In summary, the preparation method of 3-bromo-4-fluorobenzaldehyde of the present invention adopts a preparation method of continuous flow reaction, and the continuous flow reaction has higher production efficiency and reaction safety than an intermittent kettle reactor; in addition, dibromohydantoin with less toxicity is used as a brominating agent, and water is directly used as a solvent after adding a co-solvent benzyltriethylammonium chloride during the reaction, thereby avoiding the use of an organic solvent; after the reaction is complete, the slurry is collected, an appropriate amount of water is added, and the residual raw material p-fluorobenzaldehyde is removed under reduced pressure by an azeotropic method in an intermittent reactor, thereby avoiding the disproportionation side reaction during the high-temperature distillation purification of the product, thereby ensuring the purity of the product, and also avoiding the crystal loss of the product during the purification by bulk melt crystallization, thereby ensuring the yield of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 , a schematic diagram of the process flow of the tubular reaction device described in the examples of the present application;

[0028] Among them, 1. raw material tank, 2. metering pump, 3. preheating area, 4. reaction area, 5. product collection tank;

[0029] Figure 2 , the HPLC detection chromatogram of the chemical purity of 3-bromo-4-fluorobenzaldehyde in Example 1;

[0030] Figure 3 , the HPLC detection chromatogram of the chemical purity of 3-bromo-4-fluorobenzaldehyde in Example 2;

[0031] Figure 4 , the HPLC detection chromatogram of the chemical purity of 3-bromo-4-fluorobenzaldehyde in Example 3;

[0032] Figure 5 , HPLC detection chromatogram of chemical purity of 3-bromo-4-fluorobenzaldehyde in Comparative Example 1. DETAILED DESCRIPTION

[0033] The above contents of the present invention are further described in detail below through implementations represented by several specific examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following specific implementations. All technologies tested based on the above contents of the present invention belong to the scope of the present invention.

[0034] Example 1: Synthesis of 3-bromo-4-fluorobenzaldehyde

[0035] The first stage: (tubular reactor) bromination reaction

[0036] 1. 1650 g of dibromohydantoin, 50 g of benzyltriethylammonium chloride, 4000 g of 40% sulfuric acid and 1240 g of p-fluorobenzaldehyde are added to the raw material tank 1. The slurry in the raw material tank 1 is stirred evenly and pumped into the preheating zone 3 of the tubular reactor through the metering pump 2. The preheating zone is heated to 120°C and the slurry is continuously pumped into the tubular reactor 4. Bromination reaction occurs in the tubular reactor at a temperature of 120°C and a residence time of 15 min.

[0037] 2. Pass the slurry into the product collection tank 5 and cool it down to 30-35°C.

[0038] Second paragraph: post-processing

[0039] 1. Add 0.1% of the slurry weight (6.94 g) of sodium sulfite to 6940 g of the slurry after the reaction, and stir for 0.5 hour.

[0040] 2. Allow the layers to stand and discard the aqueous layer.

[0041] 3. Add 10% slurry weight (694 g) of water and 2% slurry weight (138.8 g) of sodium carbonate, stir and separate the layers, and discard the water layer.

[0042] 4. Add 10% of the slurry weight (694 g) of water, stir and separate the layers, and discard the aqueous layer.

[0043] 5. Add 5% of the slurry weight (347 grams) of water to the oil layer, distill under reduced pressure at 55-60°C while stirring, distill out the water (water content is less than 0.2%) and 10% of p-fluorobenzaldehyde first, collect the residue to obtain 1930 grams of product. (The product purity reaches 99.8%, and the molar yield is 95%).

[0044] Example 2: Synthesis of 3-bromo-4-fluorobenzaldehyde

[0045] The first stage: (tubular reactor) bromination reaction

[0046] 1. 1850 g of dibromohydantoin, 50 g of benzyltriethylammonium chloride, 4000 g of 20% sulfuric acid and 1240 g of p-fluorobenzaldehyde are added to the raw material tank 1. The slurry in the raw material tank 1 is stirred evenly and pumped into the preheating zone 3 of the tubular reactor through the metering pump 2. The preheating zone is heated to 125°C and the slurry is continuously pumped into the tubular reactor 4. Bromination reaction occurs in the tubular reactor at a temperature of 125°C and a residence time of 12 min.

[0047] 2. Pass the slurry into the product collection tank 5 and cool it down to 30-35°C.

[0048] Second paragraph: post-processing

[0049] 1. Add 0.1% of the slurry weight (6.94 g) of sodium sulfite to 7140 g of the slurry after the reaction, and stir for 0.5 hour.

[0050] 2. Allow the layers to stand and discard the aqueous layer.

[0051] 3. Add 10% slurry weight (694 g) of water and 2% slurry weight (138.8 g) of sodium carbonate, stir and separate the layers, and discard the water layer.

[0052] 4. Add 10% of the slurry weight (694 g) of water, stir and separate the layers, and discard the aqueous layer.

[0053] 5. Add 5% of the slurry weight (347 grams) of water to the oil layer, distill under reduced pressure at 55-60°C while stirring, distill out the water (water content is less than 0.2%) and distill out 10% of p-fluorobenzaldehyde first, collect the residue to obtain 1927 grams of product. (The product purity reaches 99.87%, and the molar yield is 95%).

[0054] Example 3: Synthesis of 3-bromo-4-fluorobenzaldehyde

[0055] The first stage: (tubular reactor) bromination reaction

[0056] 1. 2000 g of dibromohydantoin, 50 g of benzyltriethylammonium chloride, 4000 g of 30% sulfuric acid and 1240 g of p-fluorobenzaldehyde are added to the raw material tank 1. The slurry in the raw material tank 1 is stirred evenly and pumped into the preheating zone 3 of the tubular reactor through the metering pump 2. The preheating zone is heated to 125°C and the slurry is continuously pumped into the tubular reactor 4. Bromination reaction occurs in the tubular reactor at a temperature of 125°C and a residence time of 12 min.

[0057] 2. Pass the slurry into the product collection tank 5 and cool it down to 30-35°C.

[0058] Second paragraph: post-processing

[0059] 1. Add 0.1% of the slurry weight (7.3 g) of sodium sulfite to 7290 g of the slurry after the reaction and stir for 0.5 hour.

[0060] 2. Allow the layers to stand and discard the aqueous layer.

[0061] 3. Add 10% slurry weight (730 g) of water and 2% slurry weight (146 g) of sodium carbonate, stir and separate the layers, and discard the water layer.

[0062] 4. Add 10% of the slurry weight (730 g) of water, stir and separate the layers, and discard the aqueous layer.

[0063] 5. Add 5% of the slurry weight (365g) of water to the oil layer, distill under reduced pressure at 55-60℃ with stirring, distill out the water (water content less than 0.2%) and 10% of p-fluorobenzaldehyde first, collect the residue to obtain 1933g of product. (The product purity reaches 99.79%, and the molar yield is 95%).

[0064] Comparative Example 1: (Batch Reactor) Synthesis of 3-Bromo-4-Fluorobenzaldehyde

[0065] The first stage: (intermittent reactor) bromination reaction

[0066] 1. Add 1650 g of dibromohydantoin, 50 g of benzyltriethylammonium chloride, 4000 ml of 20% sulfuric acid, and 1240 g of p-fluorobenzaldehyde to a 10-liter intermittent reactor, heat to 100°C, react for 3.5 hours to complete the bromination reaction, and cool to 30-35°C to obtain a slurry containing 3-bromo-4-fluorobenzaldehyde.

[0067] Second paragraph: post-processing

[0068] 1. Add 0.1% of the slurry weight (6.94 g) of sodium sulfite to 6940 g of the slurry after the reaction, and stir for 0.5 hour.

[0069] 2. Allow the layers to stand and discard the aqueous layer.

[0070] 3. Add 10% slurry weight (694 g) of water and 5% weight (347 g) of sodium carbonate, stir and separate into layers.

[0071] 4. Add 10% of the slurry weight (694 g) of water, stir and separate the layers.

[0072] 5. Add 15% of the weight of the slurry (1041 grams) of water to the oil layer, distill under reduced pressure at 55-60°C while stirring, evaporate the water (water content is less than 0.2%), collect the residue to obtain 1665 grams of the product. (The product purity reaches 91%, and the molar yield is 82%).

[0073]

[0074]

[0075] From the above data, it can be seen that Example 1, Example 2, and Example 3 use a continuous flow production process to prepare 3-bromo-4-fluorobenzaldehyde, which effectively solves the problems of low reaction conversion rate, serious aldehyde disproportionation by-product, long reaction cycle, high production cost, and poor product quality, and fundamentally provides a safe, efficient, and environmentally friendly new production process. Compared with Comparative Example 1 in which 3-bromo-4-fluorobenzaldehyde is prepared using an intermittent reactor, the yield and product purity of 3-bromo-4-fluorobenzaldehyde prepared by the process of the present invention are significantly better than those prepared by an intermittent reactor.

[0076] In order to better understand the technical solution of the present invention, the above further illustrates the new method of the present invention in combination with specific embodiments, but this should not be understood as the scope of the subject matter of the present invention being limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

[0077] HPLC analysis method of 3-bromo-4-fluorobenzaldehyde:

[0078] (1) Diluent: acetonitrile

[0079] (2) Test solution: Take about 12.5 mg of the product and place it in a 25 ml volumetric flask. Add diluent to dissolve and dilute to the scale, and shake well.

[0080] (3) Chromatographic conditions: octadecylsilane bonded silica gel filling column (Agilent C18 250 mm × 4.6 mm 5μ), acetonitrile / 0.02% formic acid solution (adjusted to pH 4.5 with aqueous ammonia) = 40 / 60 (v / v), flow rate 1.0 ml / min, detection wavelength 240 nm, column temperature 30°C, injection concentration 0.5 mg / ml, injection volume 10 μl.

[0081] (4) Determination method: Accurately measure blank solution, reference solution and test solution, inject them into the liquid chromatograph in sequence, and record the chromatogram.

Claims

1. A method for preparing 3-bromo-4-fluorobenzaldehyde, characterized in that: The method adopts a continuous flow reaction, uses p-fluorobenzaldehyde as a raw material, dibromohexane as a brominating agent, an aqueous sulfuric acid solution as a reaction solvent, and benzyltriethylammonium chloride as a co-solvent to carry out a bromination reaction. After the reaction is completed, the obtained reaction slurry is post-processed and purified in an intermittent reactor.

2. A method for preparing 3-bromo-4-fluorobenzaldehyde according to claim 1, characterized in that: The continuous flow reaction is adopted, comprising the following steps: (1) Add dibromohydantoin (Formula III), benzyltriethylammonium chloride, sulfuric acid aqueous solution, and p-fluorobenzaldehyde (Formula II) into a raw material tank and stir evenly; (2) pumping the slurry in the raw material tank into the preheating zone of the tubular reactor through a metering pump for preheating; (3) passing the preheated slurry into a tubular reactor for reaction to obtain a crude slurry of 3-bromo-4-fluorobenzaldehyde (Formula I); 3. The method for preparing 3-bromo-4-fluorobenzaldehyde according to claim 2, characterized in that: The crude product slurry obtained from the continuous flow reaction is post-processed and purified in a batch reactor to obtain a product, and the post-processing purification includes the following steps: (1) Adding sodium sulfite to the slurry after the reaction is completed, stirring, allowing the slurry to stand for stratification, and discarding the aqueous layer; (2) Add water and sodium carbonate to the organic layer, stir, separate the layers, and discard the aqueous layer. (3) Add water to the oil layer, distill under reduced pressure at 55-60°C with stirring, evaporate water and p-fluorobenzaldehyde by azeotropy, and collect the residue to obtain the product 3-bromo-4-fluoroformaldehyde.

4. The method for preparing 3-bromo-4-fluorobenzaldehyde according to claim 1 or 2, characterized in that: The mass concentration of the aqueous sulfuric acid solution is 20%-40%.

5. The method for preparing 3-bromo-4-fluorobenzaldehyde according to claim 4, characterized in that: The mass ratio of dibromohydantoin, benzyltriethylammonium chloride, 20%-40% sulfuric acid aqueous solution and p-fluorobenzaldehyde is 1650-2000:50:4000:1240.

6. The method for preparing 3-bromo-4-fluorobenzaldehyde according to claim 2, characterized in that: The preheating temperature in step (2) is 120-125° C., and the reaction time is 12-15 minutes.

7. The method for preparing 3-bromo-4-fluorobenzaldehyde according to claim 2, characterized in that: After the reaction in the tubular reactor in step (3) is complete, the slurry is passed into a product collection tank and cooled to 30-35°C.

8. The method for preparing 3-bromo-4-fluorobenzaldehyde according to claim 3, characterized in that: In step (1), the weight of sodium sulfite is 0.1% of the weight of the slurry, and stirring is performed for 0.5 hours; in step (2), the weight of water is 10% of the weight of the slurry, and the weight of sodium carbonate is 2.0% of the weight of the slurry; in step (3), the weight of water is 5.0% of the weight of the slurry.

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