CN115231992A - Preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone - Google Patents
Preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone Download PDFInfo
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- CN115231992A CN115231992A CN202210757834.1A CN202210757834A CN115231992A CN 115231992 A CN115231992 A CN 115231992A CN 202210757834 A CN202210757834 A CN 202210757834A CN 115231992 A CN115231992 A CN 115231992A
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- 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
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- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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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 (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, which comprises the steps of firstly adding p-fluorobenzoic acid, dichloromethane, thionyl chloride and DMF into a reaction kettle, heating to react for 6-8 h, decompressing and evaporating to remove a solvent, and adding dichloromethane to obtain a p-fluorobenzoyl chloride solution; then adding 1-chloro-4-iodobenzene, dichloromethane and a catalyst into the reaction kettle, cooling to 0-5 ℃, slowly adding the p-fluorobenzoyl chloride solution dropwise, continuing to react for 3-5h after dropwise addition, slowly adding ice water dropwise to quench the reaction, stirring for 30 min, separating out an organic phase, washing, decompressing and concentrating the organic phase, adding isopropanol, stirring and crystallizing to obtain 3 h, filtering and drying to obtain the (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone. The invention takes p-fluorobenzoic acid as a raw material, and (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone is obtained by Friedel-crafts reaction of chlorinated p-fluorobenzoic acid and 1-chloro-4-iodobenzene. The method has the advantages of cheap and easily obtained raw materials and obvious cost advantage; dangerous reactions such as nitration, diazotization and the like are not involved in the process, and the potential safety hazard is small.
Description
Technical Field
The invention discloses a preparation method of an empagliflozin intermediate (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, belonging to the field of pharmaceutical chemicals.
Background
Empagliflozin (empagliflozin), also known as empagliflozin, alegliflozin and empagliflozin, is a novel excellent oral hypoglycemic agent, namely a sodium glucose cotransporter 2 (SGLT-2) inhibitor cooperatively developed by Boringer Vargohil, germany and the American Gift company. The rate was first marketed in europe in 2014 at 5 months, in the united states and japan in 2014 at 8 months and 12 months, respectively, and in china in 2017 at 9 months. The (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone is used as a key intermediate for synthesizing the Engelliflozin, and the development of a safe and economic preparation method of the Engelliflozin is of great significance.
Patent CN102574829a reports a method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone by chlorination and friedel-crafts reaction using 2-chloro-5-iodobenzoic acid as raw material, the synthetic route is as follows:
the route uses less 2-chloro-5-iodobenzoic acid as a material, and has high price, so that the cost of the (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone prepared by the route is high.
Patent CN106699570a reports a synthetic route using o-chlorobenzoic acid as starting material, and (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone is prepared by nitration, chlorination, friedel-crafts, reduction, diazotization and iodination, and the synthetic route is as follows:
although the starting materials are cheap and easy to obtain, the process is complicated, and the process involves dangerous reactions such as nitration, diazotization and the like, so that the process has great potential safety hazards in the industrial production process.
Disclosure of Invention
The invention provides a preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone for making up the defects of the prior art.
The method comprises the steps of firstly, reacting p-fluorobenzoic acid with thionyl chloride to generate acyl chloride, and carrying out Friedel-crafts reaction with p-chloroiodobenzene under the action of an acyl chloride catalyst. Since iodine atoms have a large radius and a poor conjugation effect, the friedel-crafts reaction mainly occurs in the ortho position to chlorine.
The invention is realized by the following technical scheme:
a preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone comprises the following steps:
s1: adding p-fluorobenzoic acid (compound III), dichloromethane, thionyl chloride and DMF into a reaction kettle, heating to 35-40 ℃, reacting for 6-8 h, detecting that the p-fluorobenzoic acid is less than or equal to 5.0%, and stopping the reaction. Evaporating the solvent under reduced pressure, and adding dichloromethane to obtain a p-fluorobenzoyl chloride solution;
s2: adding 1-chloro-4-iodobenzene (compound II), dichloromethane and a catalyst into a reaction kettle, cooling to 0-5 ℃, slowly dropwise adding the p-fluorobenzoyl chloride solution, continuously reacting for 3-5h at 20-30 ℃ after dropwise adding, stopping the reaction after HPLC (high performance liquid chromatography) detects that the temperature of the 1-chloro-4-iodobenzene is less than or equal to 1.0%, slowly dropwise adding ice water to quench the reaction, stirring for 30 min, and separating out an organic phase;
s3: washing the organic phase with potassium carbonate solution and saturated sodium chloride solution in sequence, distilling off the solvent under reduced pressure, adding isopropanol, stirring at 50-60 ℃ to crystallize 3 h, filtering and drying to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone (compound I).
Further, in the step S1, the gauge pressure of the solvent is reduced and distilled off to be less than-0.095 MPa, and no fraction is distilled off at the temperature of 60 ℃ in the kettle.
Further, the catalyst in the step S2 comprises aluminum trichloride or 4A activated powder.
Further, the molar ratio of the aluminum trichloride to the p-fluorobenzoic acid is 0.95 to 1.1,4A, and the mass ratio of the activated powder to the p-fluorobenzoic acid is 2.5-3.5.
Further, the conditions of the reduced pressure evaporation and solvent removal in the step S3 are as follows: gauge pressure is less than-0.095 MPa, and no fraction is distilled at the temperature of 65 ℃ in the kettle.
Further, the drying condition in the step S3 is forced air drying at 50 ℃ for 6h.
Compared with the prior art, the invention has the advantages that:
the invention takes p-fluorobenzoic acid as a raw material, after chlorination, the p-fluorobenzoic acid and 1-chloro-4-iodobenzene are subjected to Friedel-crafts reaction to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, and the 1-chloro-4-iodobenzene can be directly obtained by iodination of chlorobenzene. The method has the advantages of cheap and easily obtained raw materials and obvious cost advantage; dangerous reactions such as nitration, diazotization and the like are not involved in the process, and the potential safety hazard is small.
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The invention will be further described with reference to the accompanying drawings.
The attached drawing is a schematic diagram of the invention.
Detailed Description
The technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. It should be apparent that the described embodiments are only some of the embodiments of the present invention, and not all of the embodiments. Thus, the following detailed description of the embodiments of the present invention, presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: preparation of Compound I
P-fluorobenzoic acid (38.5 Kg,274.8 mol), dichloromethane (193.5 Kg), thionyl chloride (42.5 Kg,357.2 mol) and DMF (198.0 g) were added to the reactor, heated to 35-40 deg.C and reacted for 6-8 h. And (5) stopping the reaction when the content of p-fluorobenzoic acid is less than or equal to 5.0 percent by HPLC detection. The solvent was distilled off under reduced pressure (gauge pressure less than-0.095 MPa, in-kettle temperature 60 ℃ without distillate), and methylene chloride (77.0 Kg) was added to obtain a p-fluorobenzoyl chloride solution.
Adding 1-chloro-4-iodobenzene (59.0 Kg 247.3 mol), dichloromethane (120.0 Kg) and aluminium trichloride (40.3 Kg 302.3 mol) into a reaction kettle, cooling to 0-5 ℃, slowly adding a p-fluorobenzoyl chloride solution at 0-5 ℃, reacting for 3-5h at 20-30 ℃, and stopping the reaction when HPLC detects that the content of 1-chloro-4-iodobenzene is less than or equal to 1.0%. Ice water (240.0 Kg) was slowly added dropwise to quench the reaction, and the mixture was stirred for 30 min to separate the organic phase. The organic phase is washed by potassium carbonate solution (8.0 percent of 100.0 zxft 3425) and saturated sodium chloride solution (100.0 zxft 3562), the solvent is distilled off under reduced pressure (gauge pressure is less than-0.095 MPa, no fraction is distilled off at the temperature of 65 ℃ in the kettle), isopropanol (153.0 Kg) is added, 3 h is crystallized by stirring at 50-60 ℃, the mixture is filtered and dried by air blowing at 50 ℃ for 6h to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone 86.0 Kg, the yield is 96.4 percent (calculated by 1-chloro-4-iodobenzene), and the HPLC purity is 99.5 percent.
Example 2: preparation of Compound I
P-fluorobenzoic acid (31.0 Kg,221.3 mol), dichloromethane (180.3 Kg), thionyl chloride (42.5 Kg,342.3 mol) and DMF (180.0 g) were added to the reactor, heated to 35-40 deg.C and reacted for 6-8 h. And (5) stopping the reaction when the content of p-fluorobenzoic acid is less than or equal to 5.0 percent by HPLC detection. The solvent was distilled off under reduced pressure (gauge pressure less than-0.095 MPa, temperature in the autoclave was 60 ℃ without distillate), and methylene chloride (70.0 Kg) was added to obtain a p-fluorobenzoyl chloride solution.
Adding 1-chloro-4-iodobenzene (50.1 Kg 210.3 mol), dichloromethane (120.0 Kg) and aluminium trichloride (29.5 Kg 221.3 mol) into a reaction kettle, cooling to 0-5 ℃, slowly adding a p-fluorobenzoyl chloride solution at 0-5 ℃, reacting for 3-5h at 20-30 ℃, and stopping the reaction when HPLC detects that the content of 1-chloro-4-iodobenzene is less than or equal to 1.0%. Ice water (240.0 Kg) was slowly added dropwise to quench the reaction, and the mixture was stirred for 30 min to separate the organic phase. The organic phase is washed by potassium carbonate solution (8.0 percent of 80.0 zxft 3425) and saturated sodium chloride solution (80.0 zxft 3562), the solvent is distilled off under reduced pressure (gauge pressure is less than-0.095 MPa, no fraction is distilled off at the temperature of 65 ℃ in the kettle), ethanol (143.0 Kg) is added, 5h is crystallized by stirring at 50-60 ℃, the mixture is filtered, and is dried by air blowing at 50 ℃ for 6 hours to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone 70.5 Kg, the yield is 93.0 percent (calculated by 1-chloro-4-iodobenzene), and the HPLC purity is 99.7 percent.
Example 3: preparation of Compound I
P-fluorobenzoic acid (38.5 Kg,274.8 mol), dichloromethane (154.5 Kg), thionyl chloride (36.0 Kg,302.3 mol), DMF (140.5 g) were added to the reactor, heated to 35-40 deg.C, reacted 6-8 h. And (5) stopping the reaction when the content of p-fluorobenzoic acid is less than or equal to 5.0 percent by HPLC detection. The solvent was distilled off under reduced pressure (gauge pressure less than-0.095 MPa, in the kettle temperature 60 ℃ without distillate), and methylene chloride (100.0 Kg) was added to obtain a p-fluorobenzoyl chloride solution.
Adding 1-chloro-4-iodobenzene (64.2 Kg 269.3 mol), dichloromethane (120.0 Kg) and 4A activated powder (96.3 Kg) into a reaction kettle, cooling to 0-5 ℃, slowly adding a p-fluorobenzoyl chloride solution at 0-5 ℃, reacting for 3-5h at 20-30 ℃, detecting by HPLC (high performance liquid chromatography) that the content of 1-chloro-4-iodobenzene is less than or equal to 1.0%, and stopping the reaction. Ice water (240.0 Kg) was slowly added dropwise to quench the reaction, stirred for 30 min and filtered. The filtrate separated the organic phase. The organic phase is washed by potassium carbonate solution (8.0 percent of 90.0 zxft 3425) and saturated sodium chloride solution (90.0 zxft 3562), the solvent is distilled off under reduced pressure (gauge pressure is less than-0.095 MPa, no fraction is distilled off at the temperature of 65 ℃ in the kettle), ethanol (150.0 Kg) is added, 5h is crystallized by stirring at 50-60 ℃, and the mixture is filtered and dried to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone 88.0 Kg, the yield is 90.6 percent (calculated by 1-chloro-4-iodobenzene), and the HPLC purity is 99.5 percent.
Example 4: preparation of Compound I
P-fluorobenzoic acid (38.5 Kg,274.8 mol), dichloromethane (154.5 Kg), thionyl chloride (37.6 Kg,316.0 mol) and DMF (140.5 g) were added to the reactor, heated to 35-40 deg.C and reacted at 6-8 h. And (5) stopping the reaction when the content of p-fluorobenzoic acid is less than or equal to 5.0 percent by HPLC detection. The solvent was distilled off under reduced pressure (gauge pressure less than-0.095 MPa, temperature in the autoclave was 60 ℃ C. Without distillation), and methylene chloride (130.0 Kg) was added to obtain a p-fluorobenzoyl chloride solution.
Adding 1-chloro-4-iodobenzene (64.2 Kg 269.3 mol), dichloromethane (220.0 Kg) and 4A activated powder (134.8 Kg) into a reaction kettle, cooling to 0-5 ℃, slowly dropwise adding the p-fluorobenzoyl chloride solution, controlling the temperature to be 20-30 ℃ in the process, continuously reacting for 3-5h after the dropwise adding is finished, and stopping the reaction by detecting that the content of 1-chloro-4-iodobenzene is less than or equal to 1.0% by HPLC. Ice water (240.0 Kg) was slowly added dropwise to quench the reaction, stirred for 30 min and filtered. The filtrate separated the organic phase. The organic phase is washed by potassium carbonate solution (8.0 percent of 120.0 Kg) and saturated sodium chloride solution (120.0 Kg) in sequence, the organic phase is concentrated under reduced pressure, isopropanol (180.0 Kg) is added, 5h is stirred and crystallized at 50-60 ℃, and the mixture is filtered and dried to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone 94.0 Kg, the yield is 96.8 percent (calculated by 1-chloro-4-iodobenzene), and the HPLC purity is 99.6 percent.
Example 5: preparation of Compound I
P-fluorobenzoic acid (45.0 Kg,321.2 mol), dichloromethane (210.5 Kg), thionyl chloride (42.0 Kg,353.3 mol) and DMF (190.5 g) were added into a reaction kettle, heated to reflux, and reacted at 6-8 h. And (5) stopping the reaction when the content of p-fluorobenzoic acid is less than or equal to 5.0 percent by HPLC detection. The solvent was distilled off under reduced pressure, and methylene chloride (115.0 Kg) was added to give a p-fluorobenzoyl chloride solution.
Adding 1-chloro-4-iodobenzene (72.8 Kg 305.1mol), dichloromethane (220.0 Kg) and 4A activated powder (135.0 Kg) into a reaction kettle, cooling to 0-5 ℃, slowly dropwise adding the p-fluorobenzoyl chloride solution, controlling the temperature to be 20-30 ℃ in the process, continuously reacting for 3-5h after the dropwise adding is finished, and stopping the reaction by detecting that the content of 1-chloro-4-iodobenzene is less than or equal to 1.0% by HPLC. Ice water (300.0 Kg) was slowly added dropwise to quench the reaction, stirred for 30 min and filtered. The filtrate separated the organic phase. Washing the organic phase with potassium carbonate solution (8.0% 150.0 zxft 3425) and saturated sodium chloride solution (150.0 zxft 3562), concentrating the organic phase under reduced pressure, adding isopropanol (180.0 Kg), stirring at 50-60 deg.C for crystallization 5h, filtering, and drying to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone 103.0 Kg with 93.6% yield (based on 1-chloro-4-iodobenzene) and 99.6% HPLC purity)
Example 6: preparation of Compound II
Compound II can be prepared by directly iodinating compound IV (see Synthetic Communications,2004, 34 (15): 2829-2833; bulletin of the Chemical Society of Japan,2000, 73 (4): 951-956) by the following specific method:
adding sodium periodate (13.6 Kg 63.5 mol), iodine (44.0 Kg 173.2 mol), acetic acid (303.1 Kg) and acetic anhydride (155.8 Kg) into a reaction kettle, stirring for 30 min, slowly adding concentrated sulfuric acid (448.4 Kg) at the temperature of 5-10 ℃, adding chlorobenzene (45.5 Kg 404.2 mol), reacting at room temperature for 10-20 h, and stopping the reaction when HPLC chlorobenzene is less than or equal to 1.0%. Sodium sulfite solution (30.0 Kg dissolved in 300L ice water) was slowly added to quench the reaction, stirred for 1h, filtered, and the solid was purified with acetone to give 1-chloro-4-iodobenzene, 66.0Kg, yield 68.5%, HPLC purity 99.0%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone is characterized by comprising the following steps: the method comprises the following steps:
s1: adding p-fluorobenzoic acid (compound III), dichloromethane, thionyl chloride and DMF into a reaction kettle, heating to 35-40 ℃, reacting for 6-8 h, detecting that the p-fluorobenzoic acid is less than or equal to 5.0%, and stopping the reaction;
decompressing and distilling off the solvent, and adding dichloromethane (77.0 Kg) to obtain a p-fluorobenzoyl chloride solution;
s2: adding 1-chloro-4-iodobenzene (compound II), dichloromethane and a catalyst into a reaction kettle, cooling to 0-5 ℃, slowly dropwise adding the p-fluorobenzoyl chloride solution, continuously reacting for 3-5h at 20-30 ℃ after dropwise adding, stopping the reaction after HPLC (high performance liquid chromatography) detects that the temperature of the 1-chloro-4-iodobenzene is less than or equal to 1.0%, slowly dropwise adding ice water to quench the reaction, stirring for 30 min, and separating out an organic phase;
s3: washing the organic phase with potassium carbonate solution and saturated sodium chloride solution in sequence, distilling off the solvent under reduced pressure, adding isopropanol, stirring at 50-60 ℃ to crystallize 3 h, filtering and drying to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone (compound I).
2. The process according to claim 1 for the preparation of (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone, wherein: in the step S1, the gauge pressure of the solvent is reduced and distilled off to be less than-0.095 MPa, and the temperature in the kettle is 60 ℃ without fraction.
3. The process according to claim 1 for the preparation of (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone, wherein: and the catalyst in the step S2 comprises aluminum trichloride or 4A activated powder.
4. The process according to claim 3, wherein the reaction is carried out in the presence of (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone: the molar ratio of the aluminum trichloride to the p-fluorobenzoic acid is 0.95-1.1, 4A, and the mass ratio of the activated powder to the p-fluorobenzoic acid is 2.5-3.5.
5. The process according to claim 1 for the preparation of (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone, wherein: the conditions of the reduced pressure evaporation and solvent removal in the step S3 are as follows: gauge pressure is less than-0.095 MPa, and no fraction is distilled at the temperature of 65 ℃ in the kettle.
6. The process according to claim 1 for the preparation of (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone, wherein: and in the step S3, the drying condition is 50 ℃ forced air drying for 6h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0600318A1 (en) * | 1992-11-29 | 1994-06-08 | Hoechst Aktiengesellschaft | Asymmetric, halogenated benzophenones and process for their preparation |
| CN102574829A (en) * | 2009-09-30 | 2012-07-11 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| CN104610035A (en) * | 2014-12-31 | 2015-05-13 | 东莞市长安东阳光铝业研发有限公司 | Method for preparing high-purity 4,4'-difluorobenzophenone |
| CN106699570A (en) * | 2016-11-17 | 2017-05-24 | 山东铂源药业有限公司 | Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone |
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2022
- 2022-06-30 CN CN202210757834.1A patent/CN115231992A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0600318A1 (en) * | 1992-11-29 | 1994-06-08 | Hoechst Aktiengesellschaft | Asymmetric, halogenated benzophenones and process for their preparation |
| CN102574829A (en) * | 2009-09-30 | 2012-07-11 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| CN104610035A (en) * | 2014-12-31 | 2015-05-13 | 东莞市长安东阳光铝业研发有限公司 | Method for preparing high-purity 4,4'-difluorobenzophenone |
| CN106699570A (en) * | 2016-11-17 | 2017-05-24 | 山东铂源药业有限公司 | Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone |
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