A synthesis process of dapagliflozin intermediate

Abstract

The present invention relates to a synthesis process of a dapagliflozin intermediate, belonging to the technical field of drug synthesis. In order to solve the problem of high production cost, a synthesis process of a dapagliflozin intermediate is provided, the method comprising: in an organic solvent, acylation reaction of p-bromophenol and 4-ethoxybenzonitrile under the catalysis of Lewis acid to generate 5-bromo-2-hydroxy-4'-ethoxybenzophenone, reduction reaction of 5-bromo-2-hydroxy-4'-ethoxybenzophenone to generate 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane, halogenation of 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane to obtain the final product 5-bromo-2-chloro-4'-ethoxydiphenylmethane in an organic solvent; the present invention as a whole has the advantages of low production cost, high product yield, and environmental friendliness.

Description

Technical Field

[0001] The invention relates to a synthesis process of a dapagliflozin intermediate, and belongs to the field of preparation of pharmaceutical intermediates. Background Art

[0002] Dapagliflozin is being studied by Bristol-Myers Squibb and AstraZeneca as a potential treatment for type 1 and type 2 diabetes. It is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and is suitable for patients with type 2 diabetes as an adjunct to diet and exercise to improve blood sugar control. It works by inhibiting the sodium-glucose transporter 2 to prevent glucose from being reabsorbed into the blood, allowing excess glucose to be excreted from the body through the urine. Used alone or in combination with other drugs, it can significantly reduce HbA1c and fasting blood sugar in patients with type 2 diabetes.

[0003] 5-Bromo-2-chloro-4'-ethoxydiphenylmethane is an important intermediate for the preparation of dapagliflozin, and its chemical structure is shown below:

[0004]

[0005] Patent document WO2010022313 discloses a preparation process of SGLT2 inhibitors, using 5-bromo-2-chloro-benzoic acid as a raw material, undergoing Friedel-Crafts acylation reaction with phenethyl ether to generate 5-bromo-2-chloro-4'-ethoxybenzophenone, which is then reduced with sodium borohydride to obtain a dapagliflozin intermediate. AlCl3 is used multiple times during the reaction to catalyze the reaction, which requires a strict anhydrous environment to be maintained, and all of the reactions need to be separated and removed, greatly increasing the production cost. The specific reaction formula is shown below:

[0006]

[0007] Patent document CN104478670B discloses a method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane, which uses o-methylaniline as a starting material, undergoes a benzene ring bromination reaction under NBS catalysis to generate 4-bromo-2-methylaniline, undergoes a Sandmeyer reaction after diazotization to generate 5-bromo-2-chlorotoluene, and undergoes a halogenation reaction at the benzyl position in the presence of AIBN to generate 5-bromo-2-chlorobenzyl chloride, which undergoes a Friedel-Crafts alkylation reaction with phenethyl ether to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane. In this scheme, AIBN is used in the benzylation halogenation reaction, and highly toxic cyanide is produced during the reaction, which is easy to pollute the environment. The specific reaction formula is as follows:

[0008]

[0009] It can be seen from the above literature that the common disadvantages are high production cost, great environmental pollution and low yield.

[0010] Therefore, there is an urgent need to find a preparation method with low production cost, environmental friendliness and high product yield. Summary of the invention

[0011] In view of the defects existing in the above prior art, the present invention provides a synthesis process of dapagliflozin intermediates, and solves the problem of reducing production costs, reducing environmental pollution and increasing product yield.

[0012] The object of the present invention is achieved by the following technical scheme, a synthesis process of a dapagliflozin intermediate, the method comprising the following steps:

[0013] S1: In an organic solvent, p-bromophenol and 4-ethoxybenzonitrile are subjected to an acylation reaction under the catalysis of Lewis acid to generate 5-bromo-2-hydroxy-4'-ethoxybenzophenone;

[0014] S2: subjecting 5-bromo-2-hydroxy-4'-ethoxybenzophenone to a reduction reaction to generate 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane;

[0015] S3: In an organic solvent, 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane is halogenated to obtain the final product 5-bromo-2-chloro-4'-ethoxydiphenylmethane.

[0016] In the scheme of the present invention, 4-ethoxybenzonitrile is used as a starting material to undergo a Hoesch reaction with p-bromophenol. The catalyst used in the reaction is a Lewis acid but does not need to be aluminum chloride. The obtained product 5-bromo-2-hydroxy-4'-ethoxybenzophenone undergoes a reduction reaction to remove the carbonyl group to obtain 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane, which is then subjected to a halogenation reaction to obtain the final product. The requirements for the reaction environment and reaction conditions in the entire reaction process are relatively low, the threat to the environment is relatively small, the equipment cost and post-processing cost invested are relatively small, and the yield of the product is relatively high.

[0017] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the organic solvent in step S1 can be selected from chlorobenzene or dioxane. Most preferably, the yield is the highest when chlorobenzene is selected as the reaction solvent.

[0018] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the Lewis acid in step S1 can be calcium chloride or boron trifluoride. Most preferably, the product purity is higher when calcium chloride is used.

[0019] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the reaction temperature in step S1 is 80-100° C. Most preferably, the reaction rate is maximum when the reaction temperature is 100° C.

[0020] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, hydrogen chloride gas needs to be introduced during the reaction process in step S1.

[0021] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the organic solvent in step S2 is one of methanol or ethanol. Most preferably, the reaction rate is the highest when methanol is used as the reaction solvent.

[0022] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the reducing agent in step S2 can be sodium borohydride or lithium aluminum hydride. Most preferably, the reaction yield is higher when lithium aluminum hydride is used as the reducing agent.

[0023] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the reaction temperature in step S2 is -5 to 0° C. Most preferably, when the reaction temperature is -5° C., the product purity is higher.

[0024] In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the halogenation reaction catalyst in step S3 is phosphorus trichloride. In the above-mentioned method for preparing the dapagliflozin intermediate, preferably, the amount of phosphorus trichloride added in step S3 is 3 times that of the reaction substrate.

[0025] In summary, compared with the prior art, the present invention has the following advantages:

[0026] In the present invention, 4-ethoxybenzonitrile and p-bromophenol are used as starting materials, the reaction route is short, and reagents such as aluminum chloride and AIBN are not used in the reaction process, so the difficulty of post-reaction treatment is reduced, and the reaction conditions and requirements and the pollution to the environment are also reduced, thereby reducing the production cost and improving the yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the synthetic route of the present invention. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.

[0029] Example 1

[0030] In a three-necked flask, 73.59 g of 4-ethoxybenzonitrile, 400 ml of chlorobenzene, 86.5 g of p-bromophenol, 50 ml of boron trichloride and 25.8 g of calcium chloride were added, and dry hydrogen chloride gas was introduced. The temperature was raised to 100°C for reaction for 2 hours. After the reaction was completed, the introduction of hydrogen chloride gas was stopped, the mixture was cooled to room temperature, the reaction was quenched, stirred for 30 minutes, and allowed to stand for stratification. The aqueous layer was extracted once with 200 ml of chlorobenzene, the organic layers were combined, and washed once with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolvated to dryness under reduced pressure, recrystallized with ethyl acetate, filtered, and dried to obtain 138.9 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone. The product yield was 86.5%, and the product purity was 99.4%.

[0031] Example 2

[0032] 64.23 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone was placed in a beaker, added to 300 ml of ethanol, cooled to -5 ° C, 15.1 g of lithium chloride was added, 18.9 g of sodium borohydride was added in batches, reacted at room temperature for 1 h, heated to 70 ° C for 2 h, cooled to room temperature, ammonium chloride was added to quench the reaction, part of the ethanol aqueous solution was recovered under reduced pressure, 200 ml of ethyl acetate and 200 ml of water were added, stirred for 30 minutes, allowed to stand for stratification, the aqueous layer was extracted with 200 ml of ethyl acetate, the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolventized to dryness, recrystallized, filtered and dried to obtain 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane 57.14 g, the product yield was 93%, and the product purity was 99.4%.

[0033] Example 3

[0034] 61.44 g of 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane was placed in a reaction vessel, 400 ml of tetrahydrofuran was added, and the mixture was stirred for 20 min. 82.4 g of phosphorus trichloride was added, and the temperature was raised to 120 ° C. The reaction was stirred for 1 h. After the reaction was completed, the temperature was lowered to quench the reaction, ice water was added to cool the reaction solution, and the layers were allowed to stand for stratification. 200 ml of ethyl acetate was added to the aqueous layer for extraction, and the organic phases were combined and washed with saturated brine. The organic layer was desolvated under reduced pressure, recrystallized, filtered and dried to obtain 55.68 g of 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The product yield was 85.5%, and the product purity was 99%.

[0035] Example 4

[0036] In a three-necked flask, 73.59 g of 4-ethoxybenzonitrile, 400 ml of dioxane, 86.5 g of p-bromophenol, 50 ml of boron trichloride and 25.8 g of calcium chloride were added, and dry hydrogen chloride gas was introduced. The temperature was raised to 100° C. and the reaction was reacted for 2 hours. After the reaction was completed, the introduction of hydrogen chloride gas was stopped, and the mixture was cooled to room temperature to quench the reaction. The mixture was stirred for 30 minutes and allowed to stand for stratification. The aqueous layer was extracted once with 200 ml of chlorobenzene, and the organic layers were combined and washed once with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure, recrystallized with ethyl acetate, filtered and dried to obtain 130.4 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone. The yield of the product was 81.2% and the purity of the product was 98.8%.

[0037] Example 5

[0038] In a three-necked flask, 73.59 g of 4-ethoxybenzonitrile, 400 ml of chlorobenzene, 86.5 g of p-bromophenol, 50 ml of boron trichloride and 16.97 g of boron trifluoride were added, and dry hydrogen chloride gas was introduced. The temperature was raised to 100° C. and the reaction was reacted for 2 hours. After the reaction was completed, the introduction of hydrogen chloride gas was stopped, the mixture was cooled to room temperature, the reaction was quenched, stirred for 30 minutes, and allowed to stand for stratification. The aqueous layer was extracted once with 200 ml of chlorobenzene, the organic layers were combined, and washed once with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolvated to dryness under reduced pressure, recrystallized with ethyl acetate, filtered, and dried to obtain 129.27 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone. The product yield was 80.5%, and the product purity was 99.1%.

[0039] Example 6

[0040] In a three-necked flask, 73.59 g of 4-ethoxybenzonitrile, 400 ml of chlorobenzene, 86.5 g of p-bromophenol, 50 ml of boron trichloride and 25.8 g of calcium chloride were added, and dry hydrogen chloride gas was introduced. The temperature was raised to 80°C for reaction for 2 h. After the reaction was completed, the introduction of hydrogen chloride gas was stopped, the mixture was cooled to room temperature, the reaction was quenched, stirred for 30 minutes, and allowed to stand for stratification. The aqueous layer was extracted once with 200 ml of chlorobenzene, the organic layers were combined, and washed once with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolvated to dryness under reduced pressure, recrystallized with ethyl acetate, filtered, and dried to obtain 131.04 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone. The product yield was 82.6%, and the product purity was 99.1%.

[0041] Example 7

[0042] 64.23 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone was placed in a beaker, added to 300 ml of methanol, cooled to -5 ° C, 15.1 g of lithium chloride was added, 18.9 g of sodium borohydride was added in batches, reacted at room temperature for 1 h, heated to 70 ° C for 2 h, cooled to room temperature, ammonium chloride was added to quench the reaction, part of the ethanol aqueous solution was recovered under reduced pressure, 200 ml of ethyl acetate and 200 ml of water were added, stirred for 30 minutes, allowed to stand for stratification, the aqueous layer was extracted with 200 ml of ethyl acetate, the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolventized to dryness, recrystallized, filtered and dried to obtain 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane 54.92 g, the product yield was 89.4%, and the product purity was 98.5%.

[0043] Example 8

[0044] 64.23 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone was placed in a beaker, added to 300 ml of ethanol, cooled to -5 ° C, 15.1 g of lithium chloride was added, 18.9 g of sodium borohydride was added in batches, reacted at room temperature for 1 h, heated to 70 ° C for 2 h, cooled to room temperature, ammonium chloride was added to quench the reaction, part of the ethanol aqueous solution was recovered under reduced pressure, 200 ml of ethyl acetate and 200 ml of water were added, stirred for 30 minutes, allowed to stand for stratification, the aqueous layer was extracted with 200 ml of ethyl acetate, the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolventized to dryness, recrystallized, filtered and dried to obtain 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane 57.14 g, the product yield was 93%, and the product purity was 99.4%.

[0045] Example 9

[0046] 84.9 g of 5-bromo-2-chloro-4'-ethoxybenzophenone was placed in a beaker, added to 300 ml of methanol, cooled to -5 ° C, 15.1 g of lithium chloride was added, and 11.97 g of lithium hydroxide was added in batches. The reaction was carried out at room temperature for 1 h, the temperature was raised to 70 ° C for 2 h, and the reaction was cooled to room temperature. Ammonium chloride was added to quench the reaction, and part of the ethanol aqueous solution was recovered under reduced pressure. 200 ml of ethyl acetate and 200 ml of water were added, stirred for 30 minutes, and the layers were allowed to stand for stratification. The aqueous layer was extracted with 200 ml of ethyl acetate, and the organic phases were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure, recrystallized, filtered and dried to obtain 49.58 g of 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane, with a product yield of 80.7% and a product purity of 99.2%.

[0047] Example 10

[0048] 64.23 g of 5-bromo-2-hydroxy-4'-ethoxybenzophenone was placed in a beaker, added to 300 ml of ethanol, cooled to 0 ° C, 15.1 g of lithium chloride was added, 18.9 g of sodium borohydride was added in batches, reacted at room temperature for 1 h, heated to 70 ° C for 2 h, cooled to room temperature, ammonium chloride was added to quench the reaction, part of the ethanol aqueous solution was recovered under reduced pressure, 200 ml of ethyl acetate and 200 ml of water were added, stirred for 30 minutes, allowed to stand for stratification, the aqueous layer was extracted with 200 ml of ethyl acetate, the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolvated to dryness under reduced pressure, recrystallized, filtered and dried to obtain 54.43 g of 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane, the product yield was 88.6%, and the product purity was 99%

[0049] Comparative Example

[0050] This embodiment is an embodiment of the disclosed patent CN104478670B.

[0051] (1) Preparation of 4-bromo-2-methylaniline

[0052] 8.1ml (75.4mmol) of o-toluidine was placed in a dry 250ml single-necked bottle and stirred magnetically in an ice-water bath. 13.5g (75.8mmol) of N-bromosuccinimide was dissolved in 60ml of N, N-dimethylformamide, placed in a dropping funnel and slowly dripped, maintaining the reaction solution at about 0°C, and the reaction was continued for 5h. The reaction solution was poured into 600ml of ice water, solids were precipitated, and solids were obtained by suction filtration. The aqueous phase was extracted with 50ml of ethyl acetate and concentrated to obtain a small amount of solids. The combined solids were washed with petroleum ether (25ml*3) to obtain 13.2g of solids, with a yield of 95%. The product was used directly in the next step without purification.

[0053] (2) Preparation of 5-bromo-2-chlorotoluene

[0054] Add 11.7g (63.2mmol) 4-bromo-2-methylaniline to 45ml (6mol / L) hydrochloric acid solution, stir well to form salt. Place the formed solution in an ice-salt bath, cool to below -5°C, slowly drop about 20% sodium nitrite solution (4.8g, 69.5mmol, 20ml), maintain the temperature below 0°C. Drop, add 12ml of 1,4-dioxane, stir well. Slowly add the above diazonium salt solution to 3mol / L hydrochloric acid solution (20ml) of cuprous chloride (6.7g, 66.4mmol) in an ice-water bath, and stir vigorously. After the addition is completed, stir at room temperature for 0.5h, then heat to 80°C and react for 3h. The mixture was cooled and extracted with dichloromethane (75 ml*2). The extract was washed with saturated NaHCO3 solution (150 ml), water (150 ml) and saturated brine (100 ml*2), dried over anhydrous sodium sulfate overnight and concentrated under reduced pressure to obtain 11.2 g (yield 87%) of a red-brown liquid.

[0055] (3) Preparation of 4-bromo-2-(bromomethyl)-chlorobenzene

[0056] 4.1g (20mmol) 5-bromo-2-chlorotoluene, 0.66g (4mmol) 2,2-azobisisobutyronitrile, 3.9g (22mmol) N-bromosuccinimide and 20ml chloroform were placed in a 50ml dry two-necked bottle and refluxed for 5h. The mixture was diluted with petroleum ether (75ml), the solid was filtered out, the filtrate was washed with water (100ml) and saturated brine (100ml*2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 4.1g needle-shaped crystals (yield 72%).

[0057] (4) Preparation of 5-bromo-2-chloro-4'-ethoxydiphenylmethane

[0058] Add 3.1g (10.9mmol) of 4-bromo-2-(bromomethyl)-chlorobenzene to phenethyl ether (5ml) containing zinc chloride (21.9mmol) and react at 75℃ for 6h. Cool, acidify the reaction solution with hydrochloric acid solution, extract with ethyl acetate (50ml*2), wash the organic layer with water (100ml) and saturated brine (100ml*2), and dry with anhydrous sodium sulfate. Filter to remove the desiccant, concentrate the filtrate under reduced pressure, and recrystallize the residue with ethanol to obtain 2.5g of solid, with a yield of 71%.

[0059] Compared with the synthesis method of the present invention, AIBN is used in the benzylation halogenation reaction in this comparative example, and highly toxic cyanide is produced during the reaction, which is likely to cause environmental pollution and has a low yield.

[0060] The implementation of the present invention is not limited to the above-mentioned embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and detail, and these are considered to fall within the protection scope of the present invention.

Claims

1. A synthesis process of a dapagliflozin intermediate, characterized in that: The preparation method comprises: S1: In an organic solvent, p-bromophenol and 4-ethoxybenzonitrile are subjected to an acylation reaction under the catalysis of Lewis acid to generate 5-bromo-2-hydroxy-4'-ethoxybenzophenone; S2: subjecting 5-bromo-2-hydroxy-4'-ethoxybenzophenone to a reduction reaction to generate 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane; S3: halogenating 5-bromo-2-hydroxy-4'-ethoxydiphenylmethane in an organic solvent to obtain the final product 5-bromo-2-chloro-4'-ethoxydiphenylmethane; In step S1, the organic solvent is selected from chlorobenzene or dioxane; In step S1, the Lewis acid is selected from calcium chloride or boron trifluoride; In the step S1, hydrogen chloride gas needs to be introduced during the reaction; In step S2, the organic solvent is one of methanol or ethanol; In step S2, the reducing agent is selected from sodium borohydride or lithium aluminum hydride; The halogenation reaction catalyst in step S3 is phosphorus trichloride.

2. The synthesis process of a dapagliflozin intermediate according to claim 1, characterized in that: The reaction temperature in step S1 is 80-100°C.

3. A process for synthesizing a dapagliflozin intermediate according to claim 2, characterized in that: The reaction temperature in step S2 is -5~0°C.

4. The synthesis process of a dapagliflozin intermediate according to claim 3, characterized in that: In step S3, the amount of phosphorus trichloride added is 3 times that of the reaction substrate.

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