CN115231992B - Preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone - Google Patents

Abstract

The invention discloses a preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, first p-fluorobenzoic acid, dichloromethane, thionyl chloride, DMF are added to a reactor, heated for 6-8 h, the solvent is evaporated under reduced pressure, and dichloromethane is added to obtain a p-fluorobenzoyl chloride solution; then 1-chloro-4-iodobenzene, dichloromethane, and a catalyst are added to the reactor, cooled to 0-5 ° C, and the above-mentioned p-fluorobenzoyl chloride solution is slowly added dropwise, and the addition is completed and the reaction is continued for 3-5 h, and ice water is slowly added dropwise to quench the reaction, stirred for 30 min, and the organic phase is separated, washed, and the organic phase is concentrated under reduced pressure, isopropanol is added to stir and crystallize for 3 h, filtered, and dried to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone. The present invention uses p-fluorobenzoic acid as a raw material, and after chlorination, 1-chloro-4-iodobenzene is subjected to Friedel-Crafts reaction to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone. The raw materials of this method are cheap and easy to obtain, and the cost advantage is obvious; the process does not involve dangerous reactions such as nitration and diazotization, and has little safety hazard.

Description

A preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone

Technical Field

The invention discloses a method for preparing an empagliflozin intermediate (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, belonging to the field of pharmaceutical chemical industry.

Background Art

Empagliflozin, also known as empagliflozin, is a sodium glucose cotransporter 2 (SGLT-2) inhibitor developed by Boehringer Ingelheim of Germany and Eli Lilly of the United States. It is an excellent new oral hypoglycemic drug. It was first launched in Europe in May 2014, and in the United States and Japan in August and December 2014, respectively, and in China in September 2017. (2-Chloro-5-iodophenyl)(4-fluorophenyl)methanone is a key intermediate in the synthesis of empagliflozin, and it is of great significance to develop a safe and economical preparation method for it.

Patent CN102574829A reports a method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone using 2-chloro-5-iodobenzoic acid as a raw material through chlorination and Friedel-Crafts reaction. The synthetic route is as follows:

The material 2-chloro-5-iodobenzoic acid used in this route has few suppliers and high prices, resulting in a relatively high cost for (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone prepared using this route.

Patent CN106699570A reports a synthetic route using o-chlorobenzoic acid as the starting material, and prepares (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone through nitration, chlorination, Friedel-Crafts, reduction, diazotization, and iodination. The synthetic route is as follows:

Although the starting materials of this route are cheap and easily available, the steps are complicated and the process involves dangerous reactions such as nitration and diazotization, which poses a major safety hazard in the industrial production process.

Summary of the invention

In order to make up for the deficiencies of the prior art, the present invention provides a method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone.

The method firstly reacts p-fluorobenzoic acid with thionyl chloride to generate acyl chloride, which reacts with p-chloroiodobenzene in the presence of an acyl chloride catalyst to undergo a Friedel-Crafts reaction. Since the iodine atom has a large radius and poor conjugation effect, the Friedel-Crafts reaction mainly occurs at the ortho position of chlorine.

The present invention is achieved through the following technical solutions:

A method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone comprises the following steps:

S1: Add p-fluorobenzoic acid (Compound III), dichloromethane, thionyl chloride, and DMF into a reaction kettle and heat to 35-40°C. React for 6-8 hours. When p-fluorobenzoic acid is ≤5.0%, stop the reaction. Evaporate the solvent under reduced pressure and add dichloromethane to obtain p-fluorobenzoyl chloride solution.

S2: Add 1-chloro-4-iodobenzene (Compound II), dichloromethane and catalyst into the reaction kettle, cool to 0-5 °C, slowly drop the above-mentioned p-fluorobenzoyl chloride solution, continue to react at 20-30 °C for 3-5 h after the addition is complete, stop the reaction when HPLC detects 1-chloro-4-iodobenzene ≤1.0%, then slowly drop ice water to quench the reaction, stir for 30 min, and separate the organic phase;

S3: The organic phase was washed with potassium carbonate solution and saturated sodium chloride solution in sequence, the solvent was evaporated under reduced pressure, isopropanol was added, stirred at 50-60 °C for crystallization for 3 h, filtered and dried to obtain (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (Compound I).

Furthermore, in the step S1, the solvent is evaporated under reduced pressure with a gauge pressure of <-0.095 MPa, and the temperature in the kettle is 60°C with no fraction being evaporated.

Furthermore, the catalyst in step S2 includes aluminum chloride or 4A activated powder.

Furthermore, the molar ratio of aluminum chloride to p-fluorobenzoic acid is 0.95-1.1, and the mass ratio of 4A activated powder to p-fluorobenzoic acid is 2.5-3.5.

Furthermore, the conditions for removing the solvent by distillation under reduced pressure in step S3 are: gauge pressure <-0.095MPa, the temperature in the kettle is 65°C and no fraction is distilled out.

Furthermore, the drying condition in step S3 is 50° C. forced air drying for 6 hours.

Compared with the prior art, the present invention has the following advantages:

The invention uses p-fluorobenzoic acid as a raw material, and after chlorination, it is reacted with 1-chloro-4-iodobenzene to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone through Friedel-Crafts reaction, and 1-chloro-4-iodobenzene can be directly obtained by iodination of chlorobenzene. The raw materials of the method are cheap and easy to obtain, and the cost advantage is obvious; the process does not involve dangerous reactions such as nitration and diazotization, and the safety hazard is small.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be further described below in conjunction with the accompanying drawings.

The accompanying drawing is a schematic diagram of the present invention.

DETAILED DESCRIPTION

The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Therefore, the following detailed description of the embodiments of the present invention provided in the drawings is not intended to limit the scope of the claimed invention, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making creative work belong to the scope of protection of the present invention.

Example 1: Preparation of Compound I

Add 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) to a reactor, heat to 35-40°C, and react for 6-8 hours. HPLC detection of p-fluorobenzoic acid ≤ 5.0%, stop the reaction. Evaporate the solvent under reduced pressure (gauge pressure < -0.095MPa, no fraction evaporated at 60°C in the reactor), add dichloromethane (77.0 Kg) to obtain p-fluorobenzoyl chloride solution.

1-Chloro-4-iodobenzene (59.0 Kg 247.3mol), dichloromethane (120.0 Kg), aluminum chloride (40.3 Kg302.3 mol) were added to the reactor, cooled to 0-5 ℃, and p-fluorobenzoyl chloride solution was slowly added at 0-5 ℃, and then reacted for 3-5 h at 20-30 ℃. HPLC detected that 1-chloro-4-iodobenzene was ≤1.0%, and the reaction was stopped. Ice water (240.0 Kg) was slowly added dropwise to quench the reaction, stirred for 30 min, and the organic phase was separated. The organic phase was washed with potassium carbonate solution (8.0% 100.0 Kg) and saturated sodium chloride solution (100.0 Kg) in sequence, and the solvent was evaporated under reduced pressure (gauge pressure <-0.095 MPa, the temperature in the kettle was 65°C and no fraction was evaporated), isopropanol (153.0 Kg) was added, and crystallization was stirred at 50-60°C for 3 h, filtered, and dried under air at 50°C for 6 h to obtain 86.0 Kg of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, with a yield of 96.4% (based on 1-chloro-4-iodobenzene) and a HPLC purity of 99.5%.

Example 2: Preparation of Compound Ⅰ

Add 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) to a reactor, heat to 35-40°C, and react for 6-8 hours. HPLC detection of p-fluorobenzoic acid ≤ 5.0%, stop the reaction. Evaporate the solvent under reduced pressure (gauge pressure < -0.095MPa, no fraction evaporated at 60°C in the reactor), add dichloromethane (70.0 Kg) to obtain p-fluorobenzoyl chloride solution.

1-Chloro-4-iodobenzene (50.1 Kg 210.3 mol), dichloromethane (120.0 Kg), aluminum chloride (29.5 Kg221.3 mol) were added to the reactor, cooled to 0-5 ℃, and p-fluorobenzoyl chloride solution was slowly added at 0-5 ℃, and then reacted for 3-5 h at 20-30 ℃. HPLC detection of 1-chloro-4-iodobenzene ≤1.0% stopped the reaction. Slowly add ice water (240.0 Kg) to quench the reaction, stir for 30 min, and separate the organic phase. The organic phase was washed with potassium carbonate solution (8.0% 80.0 Kg) and saturated sodium chloride solution (80.0 Kg) in sequence, and the solvent was evaporated under reduced pressure (gauge pressure <-0.095 MPa, the temperature in the kettle was 65°C and no fraction was evaporated), ethanol (143.0 Kg) was added, and the mixture was stirred and crystallized at 50-60°C for 5 h, filtered, and dried with air at 50°C for 6 h to obtain 70.5 Kg of (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone, with a yield of 93.0% (based on 1-chloro-4-iodobenzene) and a HPLC purity of 99.7%.

Example 3: Preparation of Compound I

Add p-fluorobenzoic acid (38.5 Kg, 274.8 mol), dichloromethane (154.5 Kg), thionyl chloride (36.0 Kg, 302.3 mol), and DMF (140.5 g) to a reactor, heat to 35-40°C, and react for 6-8 hours. HPLC detection of p-fluorobenzoic acid ≤ 5.0%, stop the reaction. Evaporate the solvent under reduced pressure (gauge pressure < -0.095MPa, no fraction evaporated at 60°C in the reactor), add dichloromethane (100.0 Kg) to obtain p-fluorobenzoyl chloride solution.

1-Chloro-4-iodobenzene (64.2 Kg 269.3mol), dichloromethane (120.0 Kg), and 4A activated powder (96.3 Kg) were added to the reactor, cooled to 0-5 ℃, and p-fluorobenzoyl chloride solution was slowly added at 0-5 ℃, and then reacted for 3-5 h at 20-30 ℃. When HPLC detected 1-chloro-4-iodobenzene ≤1.0%, the reaction was stopped. Ice water (240.0 Kg) was slowly added dropwise to quench the reaction, stirred for 30 min, and filtered. The filtrate was separated into an organic phase. The organic phase was washed with potassium carbonate solution (8.0% 90.0 Kg) and saturated sodium chloride solution (90.0 Kg) in sequence, and the solvent was evaporated under reduced pressure (gauge pressure <-0.095 MPa, the temperature in the kettle was 65°C and no fraction was evaporated), ethanol (150.0 Kg) was added, and crystallization was stirred at 50-60°C for 5 h, filtered, and dried to obtain 88.0 Kg of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, with a yield of 90.6% (based on 1-chloro-4-iodobenzene) and a HPLC purity of 99.5%.

Example 4: Preparation of Compound I

Add 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) to a reactor, heat to 35-40°C, and react for 6-8 hours. HPLC detection of p-fluorobenzoic acid ≤ 5.0%, stop the reaction. Evaporate the solvent under reduced pressure (gauge pressure < -0.095MPa, no fraction evaporated at 60°C in the reactor), add dichloromethane (130.0 Kg) to obtain p-fluorobenzoyl chloride solution.

1-Chloro-4-iodobenzene (64.2 Kg 269.3mol), dichloromethane (220.0 Kg), and 4A activated powder (134.8 Kg) were added to the reactor, cooled to 0-5 ℃, and the above-mentioned p-fluorobenzoyl chloride solution was slowly added dropwise. The process temperature was controlled at 20-30 ℃. After the addition was completed, the reaction was continued for 3-5 hours. When HPLC detected that 1-chloro-4-iodobenzene was ≤1.0%, the reaction was stopped. Ice water (240.0 Kg) was slowly added dropwise to quench the reaction, stirred for 30 min, and filtered. The filtrate was separated into an organic phase. The organic phase was washed with potassium carbonate solution (8.0% 120.0 Kg) and saturated sodium chloride solution (120.0 Kg) in sequence, and the organic phase was concentrated under reduced pressure. Isopropanol (180.0 Kg) was added and stirred at 50-60 °C for crystallization for 5 h. The mixture was filtered and dried to obtain 94.0 Kg of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone with a yield of 96.8% (based on 1-chloro-4-iodobenzene) and a HPLC purity of 99.6%.

Example 5: Preparation of Compound I

Add 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) to a reactor, heat to reflux, and react for 6-8 h. HPLC detection of p-fluorobenzoic acid ≤ 5.0%, stop the reaction. Evaporate the solvent under reduced pressure, add dichloromethane (115.0 Kg) to obtain a p-fluorobenzoyl chloride solution.

1-Chloro-4-iodobenzene (72.8 Kg 305.1mol), dichloromethane (220.0 Kg), 4A activated powder (135.0 Kg) were added to the reactor, cooled to 0-5 ℃, and the above-mentioned p-fluorobenzoyl chloride solution was slowly added dropwise, and the process temperature was controlled at 20-30 ℃. After the addition was completed, the reaction was continued for 3-5 hours. HPLC detection of 1-chloro-4-iodobenzene ≤1.0% stopped the reaction. Slowly add ice water (300.0 Kg) to quench the reaction, stir for 30 min, and filter. The filtrate was separated into an organic phase. The organic phase was washed with potassium carbonate solution (8.0% 150.0 Kg) and saturated sodium chloride solution (150.0 Kg) in sequence, and the organic phase was concentrated under reduced pressure. Isopropanol (180.0 Kg) was added, and the mixture was stirred and crystallized at 50-60 °C for 5 h. The mixture was filtered and dried to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone 103.0 Kg, with a yield of 93.6% (based on 1-chloro-4-iodobenzene) and a HPLC purity of 99.6%).

Example 6: Preparation of Compound II

Compound II can be prepared by direct iodination of compound IV (the preparation method is shown in Synthetic Communications, 2004, 34(15): 2829-2833; Bulletin of the Chemical Society of Japan, 2000, 73(4): 951-956). The specific method is as follows:

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) were added to the reactor, stirred for 30 min, and concentrated sulfuric acid (448.4 Kg) was slowly added at a temperature of 5-10°C, and chlorobenzene (45.5 Kg 404.2 mol) was added. The reaction was allowed to react at room temperature for 10-20 h. The HPLC chlorobenzene was ≤1.0%, and the reaction was stopped. Sodium sulfite solution (30.0 kg, dissolved in 300 L of ice water) was slowly added to quench the reaction, stirred for 1 h, filtered, and the solid was purified by acetone to obtain 1-chloro-4-iodobenzene, 66.0 Kg, with a yield of 68.5% and a HPLC purity of 99.0%.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (5)

1. A method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, characterized in that it comprises the following steps: S1: Add p-fluorobenzoic acid, i.e., compound III, dichloromethane, thionyl chloride, and DMF into a reaction kettle, heat to 35-40°C, react for 6-8 hours, and stop the reaction when the p-fluorobenzoic acid content is ≤5.0%; evaporate the solvent under reduced pressure, and add dichloromethane to obtain a p-fluorobenzoyl chloride solution; S2: Add 1-chloro-4-iodobenzene (compound II), dichloromethane and a catalyst into a reaction kettle, cool to 0-5°C, slowly drop the above-mentioned p-fluorobenzoyl chloride solution, continue to react at 20-30°C for 3-5 hours after the dropwise addition is complete, stop the reaction when HPLC detects that 1-chloro-4-iodobenzene is ≤1.0%, then slowly drop ice water to quench the reaction, stir for 30 minutes, and separate the organic phase; wherein the catalyst includes aluminum chloride or 4A activation powder; S3: The organic phase was washed with potassium carbonate solution and saturated sodium chloride solution in turn, the solvent was evaporated under reduced pressure, isopropanol was added, stirred at 50-60 °C for crystallization for 3 h, filtered, and dried to obtain (2-chloro-5-iodophenyl) (4-fluorophenyl)methanone, i.e., compound Ⅰ. 2. The method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone according to claim 1 is characterized in that: in the step S1, the solvent is evaporated under reduced pressure at a gauge pressure of <-0.095MPa and an inner temperature of 60°C until no fraction is evaporated. 3. The method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone according to claim 1, characterized in that the molar ratio of aluminum chloride to p-fluorobenzoic acid is 0.95-1.1, and the mass ratio of 4A activation powder to p-fluorobenzoic acid is 2.5-3.5. 4. The method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone according to claim 1 is characterized in that: the conditions for removing the solvent under reduced pressure in the step S3 are: gauge pressure <-0.095Mpa, kettle temperature 65°C, until no fraction is evaporated. 5. The method for preparing (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone according to claim 1, characterized in that the drying condition in step S3 is forced air drying at 50°C for 6 hours.