Preparation method of dapagliflozin impurity

Abstract

The invention relates to a dapagliflozin impurity and a preparation method thereof, 5-bromo-2-chlorobenzoic acid (IV) is used as a raw material, (5-bromo-2-chlorphenyl) (4-ethyoxyl phenyl) ketone (III) is prepared through chlorination and Friedel-Crafts acylation, (5-bromo-2-chlorphenyl) (4-ethyoxyl phenyl) methanol (II) is obtained through reduction, and the benzhydryl ether impurity (I) is obtained through condensation under the catalysis of iodine. The preparation method has the advantages of simple operation, low cost, easily available raw materials and good product purity.

Description

Technical Field

[0001] This invention relates to the field of medical chemical technology, and more specifically, to the preparation of a dapagliflozin impurity, namely the preparation of bis[(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methyl] ether. Background Technology

[0002] Dapagliflozin, chemical name: (1S)-1,5-anhydride-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucanol, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, indicated for adults with type 2 diabetes to improve glycemic control in conjunction with diet and exercise.

[0003] Existing literature has disclosed several synthetic routes for dapagliflozin, such as the route reported by Bristol-Myers Squibb Company (US20020137903A1), in which (5-bromo-2-chlorophenyl)(4-ethoxyphenyl) methyl ketone (III) is reduced to 5-bromo-2-chloro-4'-ethoxydiphenylmethane by triethylsilane in the presence of boron trifluoride diethyl ether complex, which is used for the next coupling step.

[0004] In the quality research of active pharmaceutical ingredients (APIs), identifying the types and sources of impurities and controlling their generation are crucial aspects for drug researchers. The byproduct generated during the reduction of the side chain of dapagliflozin (bis[(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methyl]ether) can be increased by factors such as feed ratio, temperature, and reaction time. Therefore, the synthesis and identification of this impurity are of great significance for the quality control and process optimization of dapagliflozin.

[0005] Currently, there are no reported methods for preparing this impurity (compound I). To effectively control the quality of dapagliflozin and reduce the risks associated with clinical use, the content of this impurity needs to be controlled during the preparation of dapagliflozin intermediates. Therefore, a method for the targeted synthesis of this impurity is needed. Summary of the Invention

[0006] This invention uses 5-bromo-2-chlorobenzoic acid (IV), a commonly used material in the synthesis of dapagliflozin and eletogliflozin, as a raw material. It prepares (5-bromo-2-chlorophenyl)(4-ethoxyphenyl) methyl ketone (III) through chlorination and Friedel-Crafts acylation, and then reduces it to obtain (5-bromo-2-chlorophenyl)(4-ethoxyphenyl) methanol (II). The methanol is then condensed under iodine catalysis to obtain diphenylmethyl ether impurity (I).

[0007] .

[0008] The preparation method includes the following steps: Condensation reaction: (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol (compound II) was subjected to a dehydration condensation reaction in the presence of elemental iodine as a catalyst to obtain compound I; the reaction was carried out under solvent-free conditions.

[0009] In some embodiments, in the condensation reaction, the molar ratio of compound II to elemental iodine is 1:0.05~0.1; preferably, the molar ratio is 1:0.07.

[0010] In some embodiments, during the condensation reaction, compound II is mixed and ground with elemental iodine before the reaction to ensure thorough mixing.

[0011] In some embodiments, the reaction temperature in the condensation reaction is 50°C to 90°C; preferably, the reaction temperature is 70°C.

[0012] In some embodiments, the condensation reaction takes 0.5 to 3 hours; preferably, the reaction takes 1 hour.

[0013] In some embodiments, the condensation reaction includes the following purification steps after the reaction is complete: a) Dissolve the reaction mixture in an organic solvent and wash away excess iodine with a reducing aqueous solution; b) After extraction, drying, and concentration, the solution is further purified by recrystallization or column chromatography. Preferably, the reducing aqueous solution is a 10% sodium thiosulfate aqueous solution.

[0014] Reduction reaction: (5-bromo-2-chlorophenyl)(4-ethoxyphenyl) methyl ketone (compound III) is reduced in an organic solvent using a reducing agent.

[0015] In some embodiments, in the reduction reaction, the reducing agent is selected from sodium borohydride; the organic solvent is selected from acetonitrile.

[0016] In some embodiments, in the reduction reaction, the molar ratio of compound III to the reducing agent is 1:1.1~1.5; the reaction is first carried out at 0℃~5℃, and then heated to room temperature.

[0017] Friedel-Crafts reaction: includes the following steps: a) 5-Bromo-2-chlorobenzoic acid reacts with an acyl chloride reagent under the action of a catalyst to generate an acyl chloride intermediate; b) The acyl chloride intermediate undergoes a Friedel-Crafts acylation reaction with phenethyl ether under Lewis acid catalysis to yield compound III. Preferably, the acyl chloride reagent is thionyl chloride, and the Lewis acid is anhydrous aluminum trichloride.

[0018] The beneficial effects of this invention are: in view of the shortcomings of the prior art, a synthetic route for the dapagliflozin impurity bis[(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methyl] ether is designed, which can rapidly, simply and efficiently prepare the impurity, and is of great significance for the quality control and research of dapagliflozin. Detailed Implementation

[0019] To better understand the content of this invention, further explanation is provided below with reference to specific embodiments. It should be understood that the following specific embodiments are for illustrative purposes only and are not intended to limit the scope of this invention. Example

[0020] Step 1) Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methyl ketone (III) Under stirring, thionyl chloride (12.37 g, 0.104 mol) and a catalytic amount of N,N-dimethylformamide (DMF, 0.1 mL) were added to a suspension of 5-bromo-2-chlorobenzoic acid (23.50 g, 0.10 mol) in chloroform (75 mL). The mixture was stirred for 2 hours, and then thionyl chloride (3.45 g, 0.029 mol) was added again. After stirring for another 15 hours, the mixture was concentrated under reduced pressure to remove excess thionyl chloride and solvent. The resulting colorless solid residue was redissolved in chloroform (150 mL). Phenylacetyl ether (12.46 g, 0.102 mol) was added to the solution at -5°C to 0°C, followed by the slow addition of anhydrous aluminum trichloride (13.47 g, 0.101 mol) in portions. After the addition was complete, the reaction mixture was heated to 5°C to 10°C and stirred for 3 hours. The reaction solution was quenched in 300 mL of ice water, allowed to stand and separate into layers. The aqueous phase was extracted three times with chloroform. The organic layers were combined and washed successively with 200 mL of 1N hydrochloric acid, water, and saturated brine. The solution was dried over sodium sulfate. After concentration under reduced pressure, the resulting solid was purified by recrystallization using a mixed solvent of n-hexane and ethyl acetate (volume ratio 4:1) to give 27.5 g of the final product as a white solid, with a yield of 81%.

[0021] Step 2) Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol(II) Add 27.50 g (0.081 mol) of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl) methyl ketone and 275 mL of acetonitrile to a three-necked flask and stir until completely dissolved. Cool the solution to 0–5 °C, then slowly add sodium borohydride (3.83 g, 0.101 mol) in portions. Continue stirring the reaction mixture at this temperature for about 30 minutes, then transfer it to room temperature and continue stirring until the reaction is complete (monitor the reaction progress by TLC). After the reaction is complete, add 50 mL of distilled water and 50 mL of saturated brine to the reaction mixture, shake thoroughly, and allow to stand for separation. Separate the organic phase and concentrate it under reduced pressure to an oily substance. Then add 150 mL of methyl tert-butyl ether to the oily substance, and slowly add 1 N hydrochloric acid dropwise with stirring, continue shaking, and allow to stand for separation. Separate the organic phase and wash with 50 mL of saturated brine, dry with sodium sulfate, filter, and concentrate to give 27.11 g of a pale yellow solid crude product, yield 98%.

[0022] Step 3) Diphenylmethyl ether impurities: Preparation of bis[(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methyl] ether (I) (5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol (10.0 g, 29.27 mmol) and elemental iodine (0.520 g, 2.05 mmol) were ground thoroughly in a mortar for 2 minutes to ensure homogeneity. The mixture was then transferred to a 100 mL sealed reaction flask and stirred at 70 °C for 1 hour. After the reaction was complete (monitored by TLC), the mixture was cooled to room temperature, dissolved in 45 mL of ethyl acetate, and washed with 75 mL of 10% sodium thiosulfate aqueous solution to remove excess iodine. The aqueous phase was extracted twice with 60 mL of ethyl acetate. All organic layers were combined, dried over sodium sulfate, filtered, concentrated, and finally purified by silica gel column chromatography (dichloromethane:n-hexane = 1:3) to obtain 9.25 g of a pale yellow solid, with a yield of 95%. 1 H-NMR (300 MHz, CDCl3) δ 7.50-7.61 (m, 2H), 7.02-7.18 (m, 8H), 6.64-6.70 (m, 4H), 5.20 (s, 2H), 3.90 (q, 4H), 1.34 (t, 6H).

Claims

1. A method for preparing a bis[(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methyl] ether (compound I), characterized in that, Includes the following steps: ； (5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol (compound II) was subjected to a dehydration condensation reaction in the presence of elemental iodine as a catalyst to obtain compound I; the reaction was carried out under solvent-free conditions.

2. The preparation method according to claim 1, characterized in that, The molar ratio of compound II to elemental iodine is 1:0.05~0.1; preferably, the molar ratio is 1:0.

07.

3. The preparation method according to claim 1, characterized in that, Before the reaction, compound II was mixed and ground with elemental iodine to ensure thorough mixing.

4. The preparation method according to claim 1, characterized in that, The reaction temperature is 50℃~90℃; preferably, the reaction temperature is 70℃.

5. The preparation method according to claim 1 or 4, characterized in that, The reaction time is 0.5 to 3 hours; preferably, the reaction time is 1 hour.

6. The preparation method according to claim 1, characterized in that, After the reaction is complete, the following purification steps are included: a) Dissolve the reaction mixture in an organic solvent and wash away excess iodine with a reducing aqueous solution; b) After extraction, drying, and concentration, the solution is further purified by recrystallization or column chromatography. Preferably, the reducing aqueous solution is a 10% sodium thiosulfate aqueous solution.

7. A method for preparing compound II, characterized in that, In an organic solvent, (5-bromo-2-chlorophenyl)(4-ethoxyphenyl) methyl ketone (compound III) is reduced using a reducing agent; wherein the reducing agent is selected from sodium borohydride; and the organic solvent is selected from acetonitrile.

8. The method according to claim 7, characterized in that, The molar ratio of compound III to the reducing agent is 1:1.1~1.5; the reaction is first carried out at 0℃~5℃, and then heated to room temperature.

9. A method for preparing compound III, characterized in that, Includes the following steps: a) 5-Bromo-2-chlorobenzoic acid reacts with an acyl chloride reagent under the action of a catalyst to generate an acyl chloride intermediate; b) The acyl chloride intermediate undergoes a Friedel-Crafts acylation reaction with phenethyl ether under Lewis acid catalysis to yield compound III. Preferably, the acyl chloride reagent is thionyl chloride, and the Lewis acid is anhydrous aluminum trichloride.

10. The use of the product obtained by the method according to any one of claims 1, 7 or 9 as a reference standard for pharmaceutical impurities, particularly in the preparation or detection of dapagliflozin.

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