CN111662166A - Preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane - Google Patents
Preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane Download PDFInfo
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- CN111662166A CN111662166A CN202010468774.2A CN202010468774A CN111662166A CN 111662166 A CN111662166 A CN 111662166A CN 202010468774 A CN202010468774 A CN 202010468774A CN 111662166 A CN111662166 A CN 111662166A
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- bromo
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- ethoxydiphenylmethane
- chloride
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- ZUNCHZBITMUSRD-UHFFFAOYSA-N 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene Chemical compound C1=CC(OCC)=CC=C1CC1=CC(Br)=CC=C1Cl ZUNCHZBITMUSRD-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- LEWYCBRUDUVOLG-UHFFFAOYSA-N 1,1,2,2-tetrafluoro-2-(1,1,2,2,3,3,4,4-octafluoro-4-iodobutoxy)ethanesulfonyl fluoride Chemical compound FC(F)(I)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)S(F)(=O)=O LEWYCBRUDUVOLG-UHFFFAOYSA-N 0.000 claims abstract description 20
- OEURLNJEQCLGPS-UHFFFAOYSA-N (5-bromo-2-chlorophenyl)-(4-ethoxyphenyl)methanone Chemical compound C1=CC(OCC)=CC=C1C(=O)C1=CC(Br)=CC=C1Cl OEURLNJEQCLGPS-UHFFFAOYSA-N 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 99
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 28
- 239000003054 catalyst Substances 0.000 claims description 27
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 24
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 18
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 16
- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 claims description 15
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 14
- 239000005457 ice water Substances 0.000 claims description 12
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 235000005074 zinc chloride Nutrition 0.000 claims description 9
- 239000011592 zinc chloride Substances 0.000 claims description 9
- CNERRGRDMYRHEV-UHFFFAOYSA-H [Cl-].[La+3].[Ce+3].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-] Chemical compound [Cl-].[La+3].[Ce+3].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-] CNERRGRDMYRHEV-UHFFFAOYSA-H 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- 238000004064 recycling Methods 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000001307 helium Substances 0.000 claims description 3
- 229910052734 helium Inorganic materials 0.000 claims description 3
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052754 neon Inorganic materials 0.000 claims description 3
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims 2
- 229910015900 BF3 Inorganic materials 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 208000012839 conversion disease Diseases 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 9
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 5
- 229960003834 dapagliflozin Drugs 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 1
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane, which is characterized by comprising the following steps: step S1, preparation of 5-bromo-2-chlorobenzoyl chloride, step S2, preparation of 5-bromo-2-chloro-4 '-ethoxybenzophenone, and step S3, preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane. The invention also discloses the 5-bromo-2-chloro-4 '-ethoxy diphenylmethane prepared by the preparation method of the 5-bromo-2-chloro-4' -ethoxy diphenylmethane. The preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane disclosed by the invention has the advantages that the traditional preparation process conditions are optimized and innovated, the product purity, the reaction conversion rate and the production efficiency are effectively improved, no special requirements are required on reaction conditions and equipment, the preparation method is suitable for industrial production, the environmental pollution is less, and the good combination of economic benefit, social benefit and ecological benefit is effectively realized.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane.
Background
With the development of economy and social progress, the living standard of people is improved year by year, the living style and the living rhythm are changed greatly, the pressure from life and work is increased, more and more people suffer from diabetes under the influence of the factors, and patients are in a youthful trend. Diabetes is another fatal disease after cancer, belongs to one of cardiovascular diseases, and brings great pain and economic burden to patients, and the requirement of appropriate drug therapy is an effective measure for relieving the pain of the patients and improving the life quality of the patients.
Dapagliflozin is a sodium-glucose cotransporter inhibitor, a C-aryl glucoside compound, chemically named: (2S,3R,4R,5S,6R) -2- [3- (4-ethoxybenzyl) -4-chlorophenyl ] -6-hydroxymethyltetrahydro-2H-pyran-3, 4, 5-triol. Dapagliflozin inhibits reabsorption of blood glucose by inhibiting renal sodium-glucose cotransporter 2, thereby regulating blood glucose levels in the body; meanwhile, the glycosylated hemoglobin level and the body weight of a patient can be obviously reduced, and the method is an important choice for the drug treatment of type 2 diabetes. The existing dapagliflozin synthesis methods are relatively centralized, and all use 5-bromo-2-chloro-4' -ethoxy diphenylmethane as a key intermediate. Therefore, the research on the synthesis method of the 5-bromo-2-chloro-4' -ethoxy diphenylmethane is of great significance.
The synthesis route of 5-bromo-2-chloro-4 '-ethoxy diphenylmethane reported in patent WO2010022313 is that starting from 2-chloro-5-bromobenzoic acid, Friedel-crafts acylation is carried out on the 2-chloro-5-bromobenzoic acid and phenetole to obtain 5-bromo-2-chloro-4' -ethoxy benzophenone, and then hydroboration reduction is carried out to obtain a product, or Et is adopted3SiH and trifluoroacetic acid system reduces carbonyl to obtain product. The two-step reaction of the route simultaneously uses Lewis acid AlCl3Catalyzed, two-step reaction of AlCl3All the components need to be separated and removed, and cannot be recycled, so that the discharge of production wastewater and the consumption of cost are increased. Furthermore, the two-step reaction respectively adopts dichloromethane and THF as solvents, so that the solvent recovery becomes difficult. In addition, the two-time post-treatment is very complicated, so that the production period is prolonged, and the production cost of a workshop is increased. Although the route is suitable for industrial production, the route is obviously not an economic synthetic route, and the preparation efficiency and the product purity are certainThe lifting space of (2).
The Chinese patent CN104478670A discloses a method for preparing 5-bromo-2-chloro-4' -ethoxy diphenylmethane by using o-toluidine as an initial raw material through bromination, diazotization chlorination, benzyl chlorination and alkylation reactions. The process route uses AIBN for benzylation, and the substance can generate extremely toxic cyanide during the reaction process and cause serious pollution.
Therefore, the development of the preparation method of the 5-bromo-2-chloro-4' -ethoxy diphenylmethane with better economic benefit, better preparation efficiency and higher product purity meets the market demand and has very important significance in promoting the development of dapagliflozin in the diabetes treatment industry.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane, which effectively improves the product purity, the reaction conversion rate and the production efficiency by optimizing and innovating the conditions of the traditional preparation process, has no special requirements on reaction conditions and equipment, is suitable for industrial production, has less pollution to the environment and effectively realizes good combination of economic benefit, social benefit and ecological benefit.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane is characterized by comprising the following steps:
step S1, preparation of 5-bromo-2-chlorobenzoyl chloride: adding 5-bromo-2-chlorobenzoic acid into dichloromethane, stirring in an ice water bath for 20-30 minutes, then dropwise adding oxalyl chloride, dropwise adding within 1-2 hours, stirring and reacting at a first reaction temperature for 8-10 hours after dropwise adding, and then performing rotary evaporation to remove a solvent and unreacted reactants to obtain 5-bromo-2-chlorobenzoyl chloride; condensing and recycling the substances removed by rotary evaporation to be used as a solvent for reutilization;
step S2, preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone: adding the 5-bromo-2-chlorobenzoyl chloride prepared in the step S1 and half of Friedel-crafts acylation catalyst into dichloromethane, stirring and reacting for 1-2 hours in an ice water mixture, then dropwise adding phenetole, dropwise adding within 1 hour, adding the other half of Friedel-crafts acylation catalyst after dropwise adding, continuously stirring and reacting for 3-5 hours, and then carrying out quenching, layering, concentration and drying treatment to obtain 5-bromo-2-chloro-4' -ethoxy benzophenone;
step S3, preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane: adding the 5-bromo-2-chloro-4 '-ethoxy benzophenone prepared in the step S2 and triethylsilane into dichloromethane, stirring and reacting for 20-30 minutes in an ice-water mixture, then adding 3-5 batches of boron trifluoride ethyl ether ethanol solution in a nitrogen or inert gas atmosphere, adding for 1-2 hours, continuing stirring and reacting for 4-6 hours, and then sequentially quenching, extracting, crystallizing, filtering, and drying in the air to obtain the 5-bromo-2-chloro-4' -ethoxy diphenylmethane.
Preferably, the molar ratio of the 5-bromo-2-chlorobenzoic acid, the dichloromethane and the oxalyl chloride in the step S1 is 1 (6-10) to (1.5-2.5).
Preferably, the first reaction temperature is 15 to 25 ℃.
Preferably, the molar ratio of the 5-bromo-2-chlorobenzoyl chloride, the Friedel-crafts acylation catalyst, the dichloromethane and the phenetole in the step S2 is 1 (1-1.5): 4-7): 1.
Preferably, the Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride according to the mass ratio of 1:0.5:1 (0.1-0.3).
Preferably, the mass ratio of the 5-bromo-2-chloro-4' -ethoxybenzophenone, the triethylsilane, the dichloromethane and the boron trifluoride diethyl etherate in the ethanol solution in the step S3 is 1 (0.4-0.6) to (5-10) to (2-4).
Preferably, the mass percentage concentration of the boron trifluoride ethyl ether ethanol solution is 10-20%.
Preferably, the inert gas is any one of helium, neon and argon.
Another object of the present invention is to provide 5-bromo-2-chloro-4 '-ethoxydiphenylmethane prepared by the method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: according to the preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane, provided by the invention, the traditional preparation process conditions are optimized and innovated, so that the product purity, the reaction conversion rate and the production efficiency are effectively improved, no special requirements are required on reaction conditions and equipment, the preparation method is suitable for industrial production, the environmental pollution is less, and the good combination of economic benefit, social benefit and ecological benefit is effectively realized; by compounding the Friedel-crafts acylation catalyst, the reaction efficiency is improved, the reaction temperature is increased, a negative temperature condition is not required to be obtained by freezing, and the public engineering expenditure is reduced; through the feeding sequence and the quantity ratio of reactants in each step, the reaction conversion rate is improved, the waste of materials is reduced, the production cost is further reduced, and the product purity is improved.
Detailed Description
A preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane is characterized by comprising the following steps:
step S1, preparation of 5-bromo-2-chlorobenzoyl chloride: adding 5-bromo-2-chlorobenzoic acid into dichloromethane, stirring in an ice water bath for 20-30 minutes, then dropwise adding oxalyl chloride, dropwise adding within 1-2 hours, stirring and reacting at a first reaction temperature for 8-10 hours after dropwise adding, and then performing rotary evaporation to remove a solvent and unreacted reactants to obtain 5-bromo-2-chlorobenzoyl chloride; condensing and recycling the substances removed by rotary evaporation to be used as a solvent for reutilization;
step S2, preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone: adding the 5-bromo-2-chlorobenzoyl chloride prepared in the step S1 and half of Friedel-crafts acylation catalyst into dichloromethane, stirring and reacting for 1-2 hours in an ice water mixture, then dropwise adding phenetole, dropwise adding within 1 hour, adding the other half of Friedel-crafts acylation catalyst after dropwise adding, continuously stirring and reacting for 3-5 hours, and then carrying out quenching, layering, concentration and drying treatment to obtain 5-bromo-2-chloro-4' -ethoxy benzophenone;
step S3, preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane: adding the 5-bromo-2-chloro-4 '-ethoxy benzophenone prepared in the step S2 and triethylsilane into dichloromethane, stirring and reacting for 20-30 minutes in an ice-water mixture, then adding 3-5 batches of boron trifluoride ethyl ether ethanol solution in a nitrogen or inert gas atmosphere, adding for 1-2 hours, continuing stirring and reacting for 4-6 hours, and then sequentially quenching, extracting, crystallizing, filtering, and drying in the air to obtain the 5-bromo-2-chloro-4' -ethoxy diphenylmethane.
Preferably, the molar ratio of the 5-bromo-2-chlorobenzoic acid, the dichloromethane and the oxalyl chloride in the step S1 is 1 (6-10) to (1.5-2.5); the first reaction temperature is 15-25 ℃.
Preferably, the molar ratio of the 5-bromo-2-chlorobenzoyl chloride, the Friedel-crafts acylation catalyst, the dichloromethane and the phenetole in the step S2 is 1 (1-1.5) to 1 (4-7); the Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride according to the mass ratio of 1:0.5:1 (0.1-0.3).
Preferably, the mass ratio of the 5-bromo-2-chloro-4' -ethoxybenzophenone, the triethylsilane, the dichloromethane and the boron trifluoride diethyl etherate in the ethanol solution in the step S3 is 1 (0.4-0.6) to (5-10) to (2-4).
Preferably, the mass percentage concentration of the boron trifluoride ethyl ether ethanol solution is 10-20%.
Preferably, the inert gas is any one of helium, neon and argon.
Another object of the present invention is to provide 5-bromo-2-chloro-4 '-ethoxydiphenylmethane prepared by the method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: according to the preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane, provided by the invention, the traditional preparation process conditions are optimized and innovated, so that the product purity, the reaction conversion rate and the production efficiency are effectively improved, no special requirements are required on reaction conditions and equipment, the preparation method is suitable for industrial production, the environmental pollution is less, and the good combination of economic benefit, social benefit and ecological benefit is effectively realized; by compounding the Friedel-crafts acylation catalyst, the reaction efficiency is improved, the reaction temperature is increased, a negative temperature condition is not required to be obtained by freezing, and the public engineering expenditure is reduced; through the feeding sequence and the quantity ratio of reactants in each step, the reaction conversion rate is improved, the waste of materials is reduced, the production cost is further reduced, and the product purity is improved.
The invention will be further described with reference to specific examples, but the scope of protection of the invention is not limited thereto:
example 1
Embodiment 1 provides a method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane, comprising the steps of:
step S1, preparation of 5-bromo-2-chlorobenzoyl chloride: adding 5-bromo-2-chlorobenzoic acid into dichloromethane, stirring in an ice water bath for 20 minutes, then dropwise adding oxalyl chloride within 1 hour, stirring and reacting at a first reaction temperature for 8 hours after dropwise adding, and then performing rotary evaporation to remove a solvent and unreacted reactants to obtain 5-bromo-2-chlorobenzoyl chloride; condensing and recycling the substances removed by rotary evaporation to be used as a solvent for reutilization;
step S2, preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone: adding the 5-bromo-2-chlorobenzoyl chloride prepared in the step S1 and half of Friedel-crafts acylation catalyst into dichloromethane, stirring and reacting for 1 hour in an ice-water mixture, then dropwise adding phenetole, completing dropwise adding within 1 hour, adding the other half of Friedel-crafts acylation catalyst after completing dropwise adding, continuously stirring and reacting for 3 hours, and then quenching, layering, concentrating and drying to obtain 5-bromo-2-chloro-4' -ethoxy benzophenone;
step S3, preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane: adding the 5-bromo-2-chloro-4 '-ethoxy benzophenone prepared in the step S2 and triethylsilane into dichloromethane, stirring and reacting for 20 minutes in an ice-water mixture, then adding 3 batches of boron trifluoride ethyl ether ethanol solution in a nitrogen atmosphere, adding for 1 hour, continuing stirring and reacting for 4 hours, and then sequentially carrying out quenching, extraction, crystallization, suction filtration and air drying to obtain the 5-bromo-2-chloro-4' -ethoxy diphenylmethane.
In the step S1, the molar ratio of the 5-bromo-2-chlorobenzoic acid to the dichloromethane to the oxalyl chloride is 1:6: 1.5; the first reaction temperature was 15 ℃.
In step S2, the molar ratio of 5-bromo-2-chlorobenzoyl chloride, friedel-crafts acylation catalyst, dichloromethane, and phenetole is 1:1:4: 1.
The Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride according to the mass ratio of 1:0.5:1: 0.1.
The mass ratio of the 5-bromo-2-chloro-4' -ethoxybenzophenone to the ethyl alcohol solution of triethylsilane, dichloromethane and boron trifluoride diethyl etherate in the step S3 is 1:0.4:5: 2; the mass percentage concentration of the boron trifluoride ethyl ether ethanol solution is 10%.
5-bromo-2-chloro-4 '-ethoxydiphenylmethane prepared according to the preparation method of 5-bromo-2-chloro-4' -ethoxydiphenylmethane.
Example 2
Example 2 provides a process for the preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane, substantially as described in example 1, except that in step S1 the molar ratio of 5-bromo-2-chlorobenzoic acid, dichloromethane, oxalyl chloride is 1:7: 1.8; the first reaction temperature is 17 ℃; in the step S2, the molar ratio of the 5-bromo-2-chlorobenzoyl chloride to the Friedel-crafts acylation catalyst to the dichloromethane to the phenetole is 1:1.3:5: 1; the Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride according to the mass ratio of 1:0.5:1: 0.15.
Example 3
Example 3 provides a process for the preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane, substantially as described in example 1, except that in step S1 the molar ratio of 5-bromo-2-chlorobenzoic acid, dichloromethane, oxalyl chloride is 1:8: 2; the first reaction temperature is 20 ℃; in step S2, the molar ratio of the 5-bromo-2-chlorobenzoyl chloride to the Friedel-crafts acylation catalyst to the dichloromethane to the phenetole is 1:1.3:5.5: 1; the Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride according to the mass ratio of 1:0.5:1: 0.2.
Example 4
Example 4 provides a process for the preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane, substantially as described in example 1, except that in step S1 the molar ratio of 5-bromo-2-chlorobenzoic acid, dichloromethane, oxalyl chloride is 1:9: 2.4; the first reaction temperature is 23 ℃; in step S2, the molar ratio of the 5-bromo-2-chlorobenzoyl chloride to the Friedel-crafts acylation catalyst to the dichloromethane to the phenetole is 1:1.4:6.5: 1; the Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride according to the mass ratio of 1:0.5:1: 0.25.
Example 5
Example 5 provides a process for the preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane, substantially as described in example 1, except that in step S1 the molar ratio of 5-bromo-2-chlorobenzoic acid, dichloromethane, oxalyl chloride is 1:10: 2.5; the first reaction temperature is 25 ℃; in the step S2, the molar ratio of the 5-bromo-2-chlorobenzoyl chloride to the Friedel-crafts acylation catalyst to the dichloromethane to the phenetole is 1:1.5:7: 1; the Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride according to the mass ratio of 1:0.5:1: 0.3.
Comparative example 1
Comparative example 1 provides a process for the preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane, which is substantially the same as in example 1, except that the friedel-crafts acylation catalyst is anhydrous aluminium chloride.
Comparative example 2
Comparative example 2 provides a preparation method of 5-bromo-2-chloro-4' -ethoxydiphenylmethane, which is substantially the same as in example 1, except that the friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, and anhydrous zinc chloride in a mass ratio of 1:0.5: 1.
Comparative example 3
Comparative example 3 provides a method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane, which is substantially the same as in example 1, except that 5-bromo-2-chlorobenzoic acid and oxalyl chloride are simultaneously added to dichloromethane in step S1.
5-bromo-2-chloro-4 '-ethoxydiphenylmethane was prepared according to the method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane described in examples 1 to 5 and comparative examples 1 to 3, and the product purity and yield were as shown in Table 1.
TABLE 1
| Item | Yield of | Purity of the product |
| Unit of | ％ | ％ |
| Example 1 | 59.7 | 98.6 |
| Example 2 | 60.2 | 99.0 |
| Example 3 | 60.5 | 99.4 |
| Example 4 | 60.9 | 99.6 |
| Example 5 | 61.2 | 99.9 |
| Comparative example 1 | 54.3 | 98.1 |
| Comparative example 2 | 54.0 | 97.4 |
| Comparative example 3 | 57.2 | 98.2 |
As can be seen from Table 1, the process for the preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane disclosed by the examples of the present invention gives higher yields and product purities as a result of the synergistic effect of the steps.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. A preparation method of 5-bromo-2-chloro-4' -ethoxy diphenylmethane is characterized by comprising the following steps:
step S1, preparation of 5-bromo-2-chlorobenzoyl chloride: adding 5-bromo-2-chlorobenzoic acid into dichloromethane, stirring in an ice water bath for 20-30 minutes, then dropwise adding oxalyl chloride, dropwise adding within 1-2 hours, stirring and reacting at a first reaction temperature for 8-10 hours after dropwise adding, and then performing rotary evaporation to remove a solvent and unreacted reactants to obtain 5-bromo-2-chlorobenzoyl chloride; condensing and recycling the substances removed by rotary evaporation to be used as a solvent for reutilization;
step S2, preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone: adding the 5-bromo-2-chlorobenzoyl chloride prepared in the step S1 and half of Friedel-crafts acylation catalyst into dichloromethane, stirring and reacting for 1-2 hours in an ice water mixture, then dropwise adding phenetole, dropwise adding within 1 hour, adding the other half of Friedel-crafts acylation catalyst after dropwise adding, continuously stirring and reacting for 3-5 hours, and then carrying out quenching, layering, concentration and drying treatment to obtain 5-bromo-2-chloro-4' -ethoxy benzophenone;
step S3, preparation of 5-bromo-2-chloro-4' -ethoxydiphenylmethane: adding the 5-bromo-2-chloro-4 '-ethoxy benzophenone prepared in the step S2 and triethylsilane into dichloromethane, stirring and reacting for 20-30 minutes in an ice-water mixture, then adding 3-5 batches of boron trifluoride ethyl ether ethanol solution in a nitrogen or inert gas atmosphere, adding for 1-2 hours, continuing stirring and reacting for 4-6 hours, and then sequentially quenching, extracting, crystallizing, filtering, and drying in the air to obtain the 5-bromo-2-chloro-4' -ethoxy diphenylmethane.
2. The method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane according to claim 1, wherein the molar ratio of 5-bromo-2-chlorobenzoic acid, dichloromethane, and oxalyl chloride in step S1 is 1 (6-10) to (1.5-2.5).
3. The method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane according to claim 1, wherein the first reaction temperature is 15 to 25 ℃.
4. The method of claim 1, wherein the molar ratio of 5-bromo-2-chloro-4' -ethoxydiphenylmethane in step S2 is 1 (1-1.5): 4-7): 1.
5. The method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane according to claim 1, wherein the Friedel-crafts acylation catalyst is prepared by mixing anhydrous aluminum chloride, anhydrous copper chloride, anhydrous zinc chloride and lanthanum cerium chloride in a mass ratio of 1:0.5:1 (0.1-0.3).
6. The method of claim 1, wherein the mass ratio of the 5-bromo-2-chloro-4' -ethoxybenzophenone to the triethylsilane to the dichloromethane to the boron trifluoride ether in ethanol in step S3 is 1 (0.4-0.6) to (5-10) to (2-4).
7. The method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane according to claim 1, wherein the concentration of boron trifluoride ethyl ether in ethanol is 10 to 20% by mass.
8. The method for preparing 5-bromo-2-chloro-4' -ethoxydiphenylmethane according to claim 1, wherein the inert gas is any one of helium, neon, and argon.
9. 5-bromo-2-chloro-4 '-ethoxydiphenylmethane produced by the process according to any one of claims 1 to 8 for producing 5-bromo-2-chloro-4' -ethoxydiphenylmethane.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
| WO2022116507A1 (en) * | 2020-12-04 | 2022-06-09 | 江苏慧聚药业有限公司 | Preparation of 4-bromo-2-(4'-ethoxy-benzyl)-1-chlorobenzene |
| CN115073271A (en) * | 2022-06-08 | 2022-09-20 | 苏州敬业医药化工有限公司 | Preparation method of 4' - (5-bromo-2-chlorobenzyl) phenol |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101790311A (en) * | 2007-08-23 | 2010-07-28 | 泰拉科斯有限公司 | Benzylbenzene derivatives and using method |
| CN102177147A (en) * | 2008-08-22 | 2011-09-07 | 泰拉科斯有限公司 | Processes for the preparation of SGLT2 inhibitors |
| CN103570510A (en) * | 2012-07-19 | 2014-02-12 | 苏州中科天马肽工程中心有限公司 | One-pot synthesis method for 5-bromo-2-chloro-4'-ethoxy diphenylmethane |
| CN103896752A (en) * | 2012-12-26 | 2014-07-02 | 上海阳帆医药科技有限公司 | Preparation method of 4-chloro-3-(4-ethoxybenzyl)benzaldehyde |
| CN104086379A (en) * | 2014-07-29 | 2014-10-08 | 安徽联创药物化学有限公司 | Method for synthesizing forxiga intermediate |
| CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
| CN107417515A (en) * | 2017-03-30 | 2017-12-01 | 上海常丰生物医药科技有限公司 | A kind of new method for synthesizing Dapagliflozin intermediate |
| CN107694557A (en) * | 2017-10-23 | 2018-02-16 | 肇庆高新区国专科技有限公司 | A kind of macro porous silica gel loaded catalyst for acylation reaction |
-
2020
- 2020-05-28 CN CN202010468774.2A patent/CN111662166A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101790311A (en) * | 2007-08-23 | 2010-07-28 | 泰拉科斯有限公司 | Benzylbenzene derivatives and using method |
| CN102177147A (en) * | 2008-08-22 | 2011-09-07 | 泰拉科斯有限公司 | Processes for the preparation of SGLT2 inhibitors |
| CN103570510A (en) * | 2012-07-19 | 2014-02-12 | 苏州中科天马肽工程中心有限公司 | One-pot synthesis method for 5-bromo-2-chloro-4'-ethoxy diphenylmethane |
| CN103896752A (en) * | 2012-12-26 | 2014-07-02 | 上海阳帆医药科技有限公司 | Preparation method of 4-chloro-3-(4-ethoxybenzyl)benzaldehyde |
| CN104086379A (en) * | 2014-07-29 | 2014-10-08 | 安徽联创药物化学有限公司 | Method for synthesizing forxiga intermediate |
| CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
| CN107417515A (en) * | 2017-03-30 | 2017-12-01 | 上海常丰生物医药科技有限公司 | A kind of new method for synthesizing Dapagliflozin intermediate |
| CN107694557A (en) * | 2017-10-23 | 2018-02-16 | 肇庆高新区国专科技有限公司 | A kind of macro porous silica gel loaded catalyst for acylation reaction |
Non-Patent Citations (1)
| Title |
|---|
| WEI MENG: "Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes", 《J. MED. CHEM.》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN111995507B (en) * | 2020-09-23 | 2022-07-22 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| WO2022116507A1 (en) * | 2020-12-04 | 2022-06-09 | 江苏慧聚药业有限公司 | Preparation of 4-bromo-2-(4'-ethoxy-benzyl)-1-chlorobenzene |
| US11565990B2 (en) | 2020-12-04 | 2023-01-31 | Wisdom Pharmaceutical Co., Ltd | Preparation of 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene |
| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
| CN115073271A (en) * | 2022-06-08 | 2022-09-20 | 苏州敬业医药化工有限公司 | Preparation method of 4' - (5-bromo-2-chlorobenzyl) phenol |
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