CN111099975A - Preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone - Google Patents
Preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
Abstract
The invention discloses a preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone, and belongs to the technical field of medicine synthesis. The method comprises the following steps: (1) directly refluxing 5-bromo-2-chlorobenzoic acid and thionyl chloride under the catalysis of DMF without a solvent to react, and evaporating excessive thionyl chloride after the reaction is finished to prepare 5-bromo-2-chlorobenzoyl chloride; (2) and (2) adding dichloromethane to the material obtained in the step (1) for dissolving, directly adding silica gel loaded aluminum trichloride, reacting with phenetole under a vacuum condition, filtering after the reaction is finished, washing the filtrate with 5% sodium bicarbonate solution and water in sequence, evaporating the solvent, and then recrystallizing by using a mixed solvent of ethanol and water to obtain the 5-bromo-2-chloro-4' -ethoxy benzophenone. The method has the advantages of small acid solvent production amount, less wastewater difficult to treat, high product purity and yield, no byproduct generation, environmental protection, simple operation and suitability for industrial production and popularization.
Description
Technical Field
The invention relates to synthesis of an antidiabetic drug dapagliflozin intermediate 5-bromo-2-chloro-4' -ethoxy benzophenone, and belongs to the technical field of medicine synthesis.
Background
Dapagliflozin (Dapagliflozin) is a novel antidiabetic drug developed by the company Baishigui and Aslicon, is the first SGLT2 inhibitor approved for the treatment of type 2 diabetes to be marketed, is an important choice in diabetic drug treatment, and is suitable for being used as an auxiliary diet and exercise in type 2 diabetic adults for improving glycemic control. The chemical name of the compound is (1S) -1, 5-anhydride-1-C- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol, and the structural formula is as follows:
the 5-bromo-2-chloro-4' -ethoxy benzophenone is a key intermediate for synthesizing dapagliflozin, and the structural formula of the intermediate is as follows:
the synthesis of 5-bromo-2-chloro-4' -ethoxybenzophenone generally adopts the preparation method reported in patent WO2003099836, and the route is as follows:
the method takes 5-bromo-2-chlorobenzoic acid as a raw material, the raw material reacts with oxalyl chloride in a dichloromethane solvent to prepare an intermediate 5-bromo-2-chlorobenzoyl chloride, and then the intermediate and phenetole are subjected to Friedel-crafts acylation reaction under the catalysis of aluminum trichloride to prepare 5-bromo-2-chloro-4' -ethoxy benzophenone, more ortho-isomer byproducts are generated in the Friedel-crafts acylation process to influence the product yield, and the byproducts are close to the target product in nature, so that the byproducts are difficult to purify and the subsequent product quality is influenced; meanwhile, a large amount of waste water containing aluminum trichloride which is difficult to treat and a large amount of recovered acidic solvent are generated in the process, and the application and popularization of the method are restricted by the huge environmental protection pressure.
CN107200683A discloses a preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone, which comprises the following steps: reacting 5-bromo-2-chlorobenzoic acid with oxalyl chloride in dichloromethane under the catalysis of DMF to obtain 5-bromo-2-chlorobenzoyl chloride; and then reacting with phenetole under the catalysis of ferric trichloride in the presence of tert-butyldimethylchlorosilane to obtain the Grignard intermediate 5-bromo-2-chloro-4' -ethoxy benzophenone, wherein the method avoids the ortho-para competition reaction in the Friedel-crafts acylation process, improves the yield of the product, but still has a large amount of acidic wastewater and solvent problems which are difficult to treat in the preparation process, and the use of tert-butyldimethylchlorosilane also improves the production cost.
CN107417515A discloses another synthesis method: using dichloromethane as a solvent, using pyridine as a catalyst, reacting 5-bromo-2-chlorobenzoic acid with thionyl chloride to obtain 5-bromo-2-chlorobenzoyl chloride, and then reacting phenetole and 5-bromo-2-chlorobenzoyl chloride in a dichloromethane system by using solid acid as a catalyst to obtain 5-bromo-2-chloro-4-ethoxy benzophenone; the method still has the problem of a small amount of by-products which are difficult to treat, and meanwhile, the acidic waste solvent generated in the technical process is difficult to directly recycle, and CN107417515A and CN107200683A are not crystallized, so that the complete removal of the phenetole with high boiling point and other salts is difficult to ensure.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to provide a preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone, which has the advantages of small generation amount of an acidic solvent, less wastewater which is difficult to treat and high product purity and yield.
A preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone comprises the following steps: (1) directly refluxing 5-bromo-2-chlorobenzoic acid and thionyl chloride under the catalysis of DMF without a solvent to react, and evaporating excessive thionyl chloride after the reaction is finished to prepare 5-bromo-2-chlorobenzoyl chloride; (2) and (2) adding dichloromethane into the material obtained in the step (1) until the material is completely dissolved, directly adding aluminum trichloride loaded by silica gel, completely reacting with phenetole under a vacuum condition, filtering after the reaction is finished, washing the filtrate with 5% sodium bicarbonate solution and water in sequence, evaporating the solvent, and then recrystallizing by using a mixed solvent of ethanol and water to obtain the 5-bromo-2-chloro-4' -ethoxy benzophenone.
The addition amount of DMF is 0.5-1% of the molar amount of 5-bromo-2-chlorobenzoic acid.
In the step (1), the molar ratio of the 5-bromo-2-chlorobenzoic acid to the thionyl chloride is 1:2-5, and the reflux reaction is carried out for 2-4 hours.
The load capacity of the silica gel loaded aluminum trichloride in the step (2) is 1.6 mmol/g; the mol ratio of the 5-bromine-2-chlorobenzoic acid to the aluminum trichloride is 1: 1.05-1.5.
The vacuum degree range in the step (2) is-0.03 MPa to-0.08 MPa; the reaction temperature is-30 ℃ to-10 ℃; the reaction time is 1-3 h.
The proportion of ethanol and water in the step (2) is 1-3:1 (V/V); the dosage of the mixed solvent is 4-8 times (v/w) of the 5-bromo-2-chlorobenzoic acid. The ethanol is a recrystallization solvent with good solubility to the product, but a single solvent is difficult to obtain high yield, and the water belongs to an anti-solvent and plays a role in improving the product yield. In the step (2), the solvent may be distilled off and then used for the subsequent reaction without recrystallization.
The silica gel loaded aluminum trichloride adopted by the invention is a Lewis acid loaded on the silica gel and keeps AlCl3On the premise of excellent catalytic property, the catalyst is converted into a novel environment-friendly catalyst through immobilization, the selectivity of Friedel-crafts acylation reaction in the preparation process of 5-bromo-2-chloro-4' -ethoxy benzophenone is greatly improved, the catalyst can be recovered through filtration after the reaction is finished, and the catalyst can be used mechanically after activation, so that resources are saved, and the problems of strong equipment corrosivity, difficult separation from products, generation of a large amount of difficult-to-treat wastewater after quenching and the like caused by traditional aluminum trichloride are solved; the vacuum condition in the Friedel-crafts acylation process ensures that the reaction can be completed, and the conversion rate of the reaction is ensured.
Due to the fact that generated HCl gas and unreacted acyl chlorination reagent residues exist after the acyl chlorination reaction in the step (1), in order to avoid influencing the subsequent reaction, the HCl gas and the unreacted acyl chlorination reagent residues are often removed by a distillation method, so that a large amount of acidic solvents containing HCl and the acyl chlorination reagent are obtained and are difficult to apply directly, and a large amount of solvent loss and salt-containing wastewater are often caused in the recovery treatment process; according to the invention, the acyl chlorination reaction is directly carried out under the solvent-free condition, and the obtained distilled and recovered unreacted thionyl chloride can be reused, so that the problems are avoided; although dichloromethane is used in the subsequent process, the finally obtained dichloromethane can be directly distilled for reuse.
The invention has the beneficial effects that:
the method does not use a solvent in the acyl chlorination process, ensures good reaction effect, avoids the generation of an acid solvent, is environment-friendly, and saves cost and energy consumption;
5-bromo-2-chloro-4' -ethoxy benzophenone is obtained in a Friedel-crafts acylation process with high selectivity; the used silica gel loaded aluminum trichloride replaces the conventional Lewis acid catalyst, thereby avoiding the generation of a large amount of waste water which is difficult to treat and being convenient for recycling;
the whole preparation process is simple to operate, the product yield can reach 94.7%, the purity can reach 99.88%, the crystallization state is good, and industrialization is easy to realize.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
The preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone comprises the steps of sequentially adding 24g (0.2mol) of thionyl chloride, 0.1ml of DMF0 and 23.5g (0.1mol) of 5-bromo-2-chlorobenzoic acid into a flask, stirring, heating, refluxing for 4 hours, and after the reaction is finished, carrying out reduced pressure distillation at 60 ℃ to remove the thionyl chloride to obtain 25.1g (yield 99%) of a yellow solid 5-bromo-2-chlorobenzoyl chloride crude product;
directly adding 100ml of dichloromethane, stirring and dissolving, cooling to-20 to-25 ℃, adding 66g of aluminium trichloride loaded on silica gel (the loading amount is 1.6mmol/g and is totally 0.105mol), controlling the vacuum degree of the system to be-0.05 MPa, standing, dropwise adding 13.4g (0.11mol) of phenetole, reacting for 2 hours, filtering, soaking and washing a filter cake by using 40ml of dichloromethane, merging to obtain filtrate, washing by using 5% sodium bicarbonate solution and water in sequence, and evaporating to remove the solvent; the obtained solid was recrystallized from a mixed solvent of ethanol and water in a volume ratio of 4 times that of the mixed solvent (ethanol to water: 3:2), and dried to obtain 31.1g of 5-bromo-2-chloro-4' -ethoxybenzophenone (total yield 91.8%, HPLC purity 99.88%).
Example 2
The preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone comprises the steps of sequentially adding 48g (0.4mol) of thionyl chloride, 0.1ml of DMF0 and 23.5g (0.1mol) of 5-bromo-2-chlorobenzoic acid into a flask, stirring, heating, refluxing for 2 hours, and after the reaction is finished, carrying out reduced pressure distillation at 60 ℃ to remove the thionyl chloride to obtain 24.9g (yield 98%) of a yellow solid 5-bromo-2-chlorobenzoyl chloride crude product;
directly adding 100ml of dichloromethane, stirring for dissolving, cooling to-10 to-15 ℃, adding 66g of aluminum trichloride loaded on silica gel (the loading amount is 1.6mmol/g and is totally 0.105mol), controlling the vacuum degree of the system to be-0.03 MPa, standing, slowly dropping 13.4g (0.11mol) of phenetole for reaction for 3 hours, filtering, soaking and washing a filter cake by using 40ml of dichloromethane, merging the filter cake into filtrate, washing by using 5% sodium bicarbonate solution and water in sequence, and evaporating to remove the solvent; the obtained solid was recrystallized from a mixed solvent of 8 times the volume of ethanol and water (the volume ratio of ethanol to water was 1:1), and dried to obtain 30.2g of 5-bromo-2-chloro-4' -ethoxybenzophenone (total yield 89.1% HPLC purity 99.47%).
Example 3
The preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone comprises the steps of sequentially adding 24g (0.2mol) of thionyl chloride, 0.1ml of DMF0 and 23.5g (0.1mol) of 5-bromo-2-chlorobenzoic acid into a flask, stirring, heating, refluxing for h, and after the reaction is finished, carrying out reduced pressure distillation at 60 ℃ to remove the thionyl chloride to obtain 25.2g (yield 99%) of a yellow solid 5-bromo-2-chlorobenzoyl chloride crude product;
directly adding 100ml of dichloromethane, stirring for dissolving, cooling to-25 to-30 ℃, adding 66g of aluminium trichloride loaded on silica gel (the loading amount is 1.6mmol/g and is totally 0.105mol), controlling the vacuum degree of the system to be-0.07 MPa, standing, slowly dropwise adding 13.4g (0.11mol) of phenetole for reacting for 4 hours, filtering, soaking and washing a filter cake by using 40ml of dichloromethane, merging the filter cake into a filtrate, washing by using 5% sodium bicarbonate solution and water in sequence, evaporating the solvent to dryness to obtain 32.1g of 5-bromo-2-chloro-4' -ethoxy benzophenone (the total yield is 94.7%, and the HPLC purity is 99.09%), and directly using the obtained product in the subsequent reaction.
Example 4
The preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone comprises the steps of sequentially adding 60g (0.5mol) of thionyl chloride, 0.1ml of DMF0 and 23.5g (0.1mol) of 5-bromo-2-chlorobenzoic acid into a flask, stirring, heating, refluxing for 3 hours, and after the reaction is finished, carrying out reduced pressure distillation at 60 ℃ to remove the thionyl chloride to obtain 24.9g (yield 98%) of a yellow solid 5-bromo-2-chlorobenzoyl chloride crude product;
directly adding 100ml of dichloromethane, stirring for dissolving, cooling to-20 to-25 ℃, adding 94.3g of silica gel-loaded aluminum trichloride (the loading amount is 1.6mmol/g and is 0.15mol in total), controlling the vacuum degree of the system to be-0.05 MPa, standing, dropwise adding 13.4g (0.11mol) of phenetole for reacting for 2 hours, filtering, soaking and washing a filter cake by using 40ml of dichloromethane, merging the filter cake into filtrate, washing by using 5% sodium bicarbonate solution and water in sequence, and evaporating to remove the solvent; the obtained solid was recrystallized from a mixed solvent of ethanol and water in a volume ratio of 4 times that of the mixed solvent (ethanol to water: 3:2), and dried to obtain 31.3g of 5-bromo-2-chloro-4' -ethoxybenzophenone (total yield 92.3%, HPLC purity 99.82%).
Example 5
The preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone comprises the steps of sequentially adding 48g (0.4mol) of thionyl chloride, 0.1ml of DMF0 and 23.5g (0.1mol) of 5-bromo-2-chlorobenzoic acid into a flask, stirring, heating, refluxing for 2 hours, and after the reaction is finished, distilling under reduced pressure at 60 ℃ to remove the thionyl chloride;
directly adding 100ml of dichloromethane, stirring for dissolving, cooling to-10 to-15 ℃, adding 75.4g of aluminum trichloride loaded on silica gel (the loading amount is 1.6mmol/g and is 0.12mol in total), controlling the vacuum degree of the system to be-0.03 MPa, standing, slowly dropping 13.4g (0.11mol) of phenetole for reaction for 4 hours, filtering, soaking and washing a filter cake by using 40ml of dichloromethane, merging into filtrate, washing by using 5% sodium bicarbonate solution and water in sequence, and evaporating to remove the solvent; the obtained solid was recrystallized from a mixed solvent of 8 times the volume of ethanol and water (the volume ratio of ethanol to water was 1:1), and dried to obtain 30.1g of 5-bromo-2-chloro-4' -ethoxybenzophenone (total yield 88.8% HPLC purity 99.87%).
Example 6
The preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone comprises the steps of sequentially adding 24g (0.2mol) of thionyl chloride, 0.1ml of DMF0 and 23.5g (0.1mol) of 5-bromo-2-chlorobenzoic acid into a flask, stirring, heating, refluxing for 4 hours, and after the reaction is finished, distilling under reduced pressure at 60 ℃ to remove the thionyl chloride;
directly adding 100ml of dichloromethane, stirring for dissolving, cooling to-25 to-30 ℃, adding 66g of aluminium trichloride loaded on silica gel (the load is 1.6mmol/g and is totally 0.105mol), controlling the vacuum degree of the system to be-0.08 MPa, standing, slowly dropwise adding 13.4g (0.11mol) of phenetole for reacting for 4 hours, filtering, soaking and washing a filter cake by using 40ml of dichloromethane, merging the filter cake into a filtrate, washing by using 5% sodium bicarbonate solution and water in sequence, evaporating the solvent to dryness to obtain 31.7g of 5-bromo-2-chloro-4' -ethoxy benzophenone (the total yield is 93.5%, the HPLC purity is 99.19%), and directly using the obtained product in the subsequent reaction.
Claims (5)
1. A preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone is characterized by comprising the following steps: the method comprises the following steps: (1) directly refluxing 5-bromo-2-chlorobenzoic acid and thionyl chloride under the catalysis of DMF without a solvent to react, and evaporating excessive thionyl chloride after the reaction is finished to prepare 5-bromo-2-chlorobenzoyl chloride; (2) and (2) adding dichloromethane into the material obtained in the step (1) until the material is completely dissolved, directly adding aluminum trichloride loaded by silica gel, completely reacting with phenetole under a vacuum condition, filtering after the reaction is finished, washing the filtrate with 5% sodium bicarbonate solution and water in sequence, evaporating the solvent, and then recrystallizing by using a mixed solvent of ethanol and water to obtain the 5-bromo-2-chloro-4' -ethoxy benzophenone.
2. The process for the preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone according to claim 1, wherein: in the step (1), the molar ratio of the 5-bromo-2-chlorobenzoic acid to the thionyl chloride is 1:2-5, and the reflux reaction is carried out for 2-4 hours.
3. The process for the preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone according to claim 1, wherein: the load capacity of the silica gel loaded aluminum trichloride in the step (2) is 1.6 mmol/g; the mol ratio of the 5-bromine-2-chlorobenzoic acid to the aluminum trichloride is 1: 1.05-1.5.
4. The process for the preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone according to claim 1, wherein: the vacuum degree range in the step (2) is-0.03 MPa to-0.08 MPa; the reaction temperature is-30 ℃ to-10 ℃; the reaction time is 1-3 h.
5. The process for the preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone according to claim 1, wherein: the proportion of ethanol and water in the step (2) is 1-3:1 (V/V); the dosage of the mixed solvent is 4-8 times (v/w) of the 5-bromo-2-chlorobenzoic acid.
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