CN111925283A - Preparation method of dapagliflozin impurity - Google Patents
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- CN111925283A CN111925283A CN202010619268.9A CN202010619268A CN111925283A CN 111925283 A CN111925283 A CN 111925283A CN 202010619268 A CN202010619268 A CN 202010619268A CN 111925283 A CN111925283 A CN 111925283A
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- C07C51/58—Preparation of carboxylic acid halides
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Abstract
The invention relates to a preparation method of dapagliflozin impurity 5-bromo-2-chloro-2' -ethoxy benzophenone, which comprises the steps of chlorination, esterification, rearrangement and alkylation reaction in sequence to obtain a target product. According to the invention, 5-bromo-2-chlorobenzoic acid ester is taken as an initial reactant, 5-bromo-2-chlorobenzoic acid phenyl ester is obtained through chlorination reaction and esterification reaction, Fries rearrangement and alkylation reaction are carried out to obtain the impurity I reaching Griflozin, the reaction conditions are mild, and the safety of the preparation process is improved; meanwhile, the preparation method provided by the invention is simple in process steps, and the product is easy to purify, so that a basis is provided for the research on related substances of dapagliflozin.
Description
Technical Field
The invention relates to a preparation method of dapagliflozin impurities, in particular to a preparation method of 5-bromo-2-chloro-2' -ethoxy benzophenone, and belongs to the field of pharmaceutical chemicals.
Background
Dapagliflozin (english name: Dapagliflozin) is chemically named (2S,3R,4R,5S,6R) -2- [3- (ethoxyphenyl ] -6-hydroxymethyltetrahydro-2H-pyran-3, 4, 5-triol Dapagliflozin (Dapagliflozin) is an oral once-a-day sodium-dependent glucose protein (SGLT2) inhibitor developed by the company bayashimasari, nobel and astrikon, and is approved by EMA and FDA respectively on day 11, month 14 and day 1, month 8 in 2012, and becomes the 2 nd FDA-approved SGLT2 inhibitor following canaglizin.
The following formula is an important intermediate 5-bromo-2-chloro-4' -ethoxy benzophenone (compound of formula VI) in the process of synthesizing dapagliflozin.
In the synthesis process, Friedel-crafts acylation reaction is involved, position isomerization is inevitably generated, and a by-product 5-bromo-2-chloro-2' -ethoxy benzophenone, namely dapagliflozin specific impurities (a compound shown in the following formula I) are generated.
Chinese patent No. CN105061373B entitled "a method for synthesizing dapagliflozin isomer impurity" (application No. CN201510561357.1) discloses a method for synthesizing the above compound i, which converts 5-bromo-2-chlorobenzoic acid into acyl chloride, and performs friedel-crafts acylation reaction with phenetole in the presence of aluminum trichloride (or zinc chloride, trifluoroacetic anhydride) to generate 5-bromo-2-chloro-2' -ethoxy benzophenone, but the method can only obtain 5% of impurity i, and the yield is extremely low. This is because, owing to the properties inherent to the friedel-crafts acylation, there are regioisomeric side reactions which make it impossible to synthesise the intermediates vi and i in a targeted manner. The existing method for synthesizing the compound I can also be that 2-chloro-5-bromobenzoic acid is dissolved in a first solvent, an acylation reagent is added, and the reaction is carried out for 1 to 8 hours at the temperature of 20 to 60 ℃ to generate acyl chloride; dissolving methoxymethylamine hydrochloride in a second solvent, adding alkali at-10 ℃, then dropwise adding an acyl chloride compound dissolved in the second solvent, keeping the temperature, stirring and reacting for 1-4 hours to obtain an amide compound; dissolving o-bromoanisole in a third solvent, adding a hexane solution of n-butyllithium at-78 ℃, then dropwise adding an amide compound dissolved in the third solvent, and carrying out reaction and post-treatment to obtain the Griflozin impurity I. The methoxy methylamine hydrochloride and the o-bromoanisole which are needed in the reaction are not easy to obtain, and the operation is complicated and the side reaction is more.
Therefore, the preparation method of 5-bromo-2-chloro-2' -ethoxy benzophenone is to be further improved.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a preparation method of dapagliflozin impurities, which can simplify operation steps, shorten reaction time and improve yield.
The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of dapagliflozin impurity I is characterized by comprising the following steps:
a preparation method of dapagliflozin impurities is characterized by comprising the following steps:
(1) adding a compound V shown in the following formula into an organic solvent, and then adding a chlorination reagent to react to obtain a compound IV shown in the following formula;
(2) under the catalysis of alkali, reacting the compound IV obtained in the step (1) with phenol to obtain a compound III shown in the following formula;
(3) placing the compound III obtained in the step (2) in an organic solvent, and carrying out Fries rearrangement reaction to obtain a compound II;
(4) performing alkylation reaction on the compound II obtained in the step (3) and bromoethane or iodoethane to obtain a compound I with the following formula, wherein the compound I is a target product 5-bromo-2-chloro-2' -ethoxy benzophenone,
wherein, X is chlorine or bromine.
Preferably, the chlorination reaction in step (1) is: and (3) placing the compound V in halogenated hydrocarbon, toluene or benzene, wherein the reaction temperature is 30-80 ℃, and the reaction time is 3-5 h.
Preferably, the chlorinating agent in the step (1) is one of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride, and the mass ratio of the chlorinating agent to the compound V is (2-4): 1, preferably (1.2-4): 1.
Preferably, in the step (2), the base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and N, N-diisopropylethylamine, and the amount ratio of the base to the compound V is (1-5): 1.
Preferably, in the step (2), the mass ratio of the phenol to the compound V is (2-5): 1.
Preferably, the rearrangement reaction in the step (3) is carried out in the presence of a catalyst, the catalyst is one of aluminum trichloride, zinc chloride and trifluoroacetic anhydride, and is further preferably aluminum trichloride, the temperature of the rearrangement reaction is 120-200 ℃, and the reaction time is 5-7 h.
Preferably, the organic solvent for the rearrangement reaction in step (3) is one of chlorobenzene, nitrobenzene, and 1,1,2, 2-tetrachloroethane.
Preferably, the molar ratio of bromoethane or iodoethane to the compound of formula III used in the alkylation reaction in step (4) is (1.5-3.5): 1.0.
Preferably, the alkylation reaction in step (4) is carried out in one of solvents of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, 1, 4-dioxane, tetrahydrofuran, and acetonitrile.
Compared with the prior art, the invention has the advantages that: the compound V is used as an initial reactant, and the compound I is obtained through chlorination, esterification, rearrangement and alkylation reactions, so that the use of expensive raw materials needing ultralow-temperature preparation is avoided; the reaction condition is mild, and the safety of the preparation process is improved; meanwhile, the preparation method provided by the invention is simple in process steps and easy to purify the product.
Drawings
FIG. 1 is an HPLC chart of Compound I in example 1 of the present invention;
FIG. 2 is a HPLC chart of a mixture of compound I and compound VI in example 1 of the present invention;
FIG. 3 is an ESI-MS diagram of Compound I in example 1 of the present invention.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1:
the preparation method of dapagliflozin impurity in the embodiment comprises the following steps:
(1) preparation of compound iii: adding 2-chloro-5-bromobenzoic acid (compound V) (23.5g,0.1mol,1.0eq) and chloroform (200mL) into a 500mL four-neck flask with a thermometer and mechanical stirring, then adding thionyl chloride (21.8mL,0.3mol, 3.0eq), stirring and reacting at 60 ℃ for 3 hours, and concentrating to dryness after the reaction is finished to obtain 25.5g of compound IV which is directly used for the next reaction;
adding phenol (18.8g,0.2mol,2.0eq) and trichloromethane (100mL) into a 250mL single-mouth bottle, stirring, controlling the reaction temperature to be-10 ℃, adding triethylamine (28mL,0.2mmoL,2.0eq), slowly dropwise adding a solution of the compound IV (10.20g,40mmoL,1.0eq) dissolved in trichloromethane (50mL), recovering the room temperature after dropwise adding is finished, and continuing to react for 3 hours; washing the reaction solution with 100mL of water, separating the solution, removing the solvent under reduced pressure, and drying in vacuum to obtain 28.1g of white solid, wherein the yield is 90%, namely a compound III;
(2) preparation of compound i: adding 6g of compound III, 100mL of chlorobenzene and 4.0g of aluminum chloride into a 250mL reaction bottle, heating in an oil bath at 150 ℃ for reaction for 5-7h, detecting by TLC (thin layer chromatography) until the reaction is finished, adding 50mL of water for quenching reaction, adding 25mL of 1moL/L hydrochloric acid, stirring for layering, washing an organic layer by using 100mL of water, then layering, and carrying out reduced pressure rotary evaporation on the organic layer to obtain an oily substance (compound II); adding 60mL of DMF, 4.8g of potassium carbonate and 3.4g of bromoethane into the residue, stirring at room temperature for reaction, adding 200mL of water and 100mL of dichloromethane into a reaction bottle after TLC detection is finished, and stirring for layering; and washing the organic layer with 100mL of water, then carrying out layering, collecting the organic layer, carrying out reduced pressure spin drying, adding 20mL of absolute ethyl alcohol, stirring, crystallizing, carrying out suction filtration, and drying to obtain a dry product 3.3 g.
Inspecting the dried product, wherein the purity of the target product is 95.8% as shown in figures 1 and 2; mass spectrometric detection As shown in FIG. 3, ESI-MS (m/z): 339[ M + H]+The sample molecular weight 338 corresponds to the target.
Example 2:
the preparation method of dapagliflozin impurity in the embodiment comprises the following steps:
(1) preparation of compound iii: in a 500mL four-necked flask equipped with a thermometer and mechanical stirring, 2-chloro-5-bromobenzoic acid (compound V) (23.5g,0.1mol,1.0eq) and toluene (200mL) were added, followed by thionyl chloride (29.2mL,0.4mol, 4.0eq) and stirred at 30 ℃ for 5 hours, after the reaction was completed, the mixture was concentrated to dryness to obtain 25.3g of compound IV, which was used directly in the next reaction;
adding phenol (14.1g,0.15mol,1.5eq) and dichloromethane (100mL) into a 250mL single-mouth bottle, stirring, controlling the reaction temperature to be-10 ℃, adding triethylamine (28mL,0.2mmoL,2.0eq), slowly dropwise adding a solution of the compound IV (10.20g,40mmoL,1.0eq) dissolved in dichloromethane (50mL), recovering the room temperature after dropwise adding is finished, and continuing to react for 3 hours; washing the reaction solution with 100mL of water, separating the solution, removing the solvent under reduced pressure, and drying in vacuum to obtain 26.5g of white solid, wherein the yield is 85%, namely the compound III;
(2) preparation of compound i: 6g of compound III, 4.0g of aluminum chloride and 50ml of 1,1,2, 2-tetrachloroethane are added into a reaction flask, and the mixture is heated in an oil bath at 150 ℃ for reaction for 5 to 7 hours, after the reaction is finished (TLC detection, developing solvent, petroleum ether: ethyl acetate: 30:1), 50ml of water is added for quenching reaction, 50ml of dichloromethane is added, and the mixture is stirred and layered. The organic layer was collected, 25ml of 1mol/l hydrochloric acid was added thereto, and the mixture was stirred to separate the layers. 50ml of 0.5mol/L sodium hydroxide solution was added to the organic layer, and the mixture was stirred for 10min and separated into layers. 20ml of 0.5mol/L sodium hydroxide solution was added to the organic layer, and the mixture was stirred and separated. The aqueous layers were combined, and 50ml of methylene chloride was added and the layers were stirred. 50ml of ethyl acetate was added to the aqueous layer, and hydrochloric acid was added dropwise to adjust the pH to 2, followed by stirring for 10 min. And (4) layering and collecting an organic layer. The aqueous layer was washed with 50ml of ethyl acetate, and the organic layers were combined and washed with 100ml of water. The organic layer was rotary-distilled under reduced pressure at 45 ℃ to give 2.2g of a residue.
To the residue were added 30ml of DMF, 2.4g of potassium carbonate, 1.7g of bromoethane, and the reaction was stirred at room temperature. After completion of the reaction (TLC assay, developing solvent, petroleum ether: ethyl acetate: 20:1), 200ml of water and 50ml of dichloromethane were added to the reaction flask, and the mixture was stirred and separated. Collecting the organic layer, drying by spinning under reduced pressure, adding 10ml absolute ethyl alcohol, stirring and crystallizing. And (5) carrying out suction filtration and drying. To obtain 1.1g of a dried product.
Example 3:
the preparation method of dapagliflozin impurity in the embodiment comprises the following steps:
(1) preparation of compound iii: adding 2-chloro-5-bromobenzoic acid (compound V) (23.5g,0.1mol,1.0eq) and chloroform (200mL) into a 500mL four-neck flask with a thermometer and mechanical stirring, then adding thionyl chloride (29.1mL,0.4mol, 4.0eq), stirring and reacting at 80 ℃ for 5 hours, and concentrating to dryness after the reaction is finished to obtain 25.9g of compound IV which is directly used for the next reaction;
adding phenol (47g,0.5mol,5.0eq) and trichloromethane (100mL) into a 250mL single-mouth bottle, stirring, controlling the reaction temperature to be-10 ℃, adding triethylamine (70mL,0.5mmoL,5.0eq), slowly dropwise adding a solution of the compound IV (10.20g,40mmoL,1.0eq) dissolved in trichloromethane (50mL), recovering the room temperature after dropwise adding is finished, and continuing to react for 4 hours; washing the reaction solution with 100mL of water, separating the solution, removing the solvent under reduced pressure, and drying in vacuum to obtain 37g of white solid, wherein the yield is 85%, namely the compound III;
(2) preparation of compound i: adding 6g of compound III, 100mL of chlorobenzene and 4.0g of aluminum chloride into a 250mL reaction bottle, heating in an oil bath at 150 ℃ for reaction for 5-7h, detecting by TLC (thin layer chromatography) until the reaction is finished, adding 50mL of water for quenching reaction, adding 25mL of 1moL/L hydrochloric acid, stirring for layering, washing an organic layer by using 100mL of water, then layering, and carrying out reduced pressure rotary evaporation on the organic layer to obtain an oily substance (compound II); adding 60mL of DMF, 1.2g of potassium carbonate and 1.0g of bromoethane into the residue, stirring at room temperature for reaction, adding 200mL of water and 100mL of dichloromethane into a reaction bottle after TLC detection is finished, and stirring for layering; and washing the organic layer with 100mL of water, then carrying out layering, collecting the organic layer, carrying out reduced pressure spin drying, adding 20mL of absolute ethyl alcohol, stirring, crystallizing, carrying out suction filtration, and drying to obtain 0.9g of a dry product.
Claims (9)
1. A preparation method of dapagliflozin impurities is characterized by comprising the following steps:
(1) adding a compound V shown in the following formula into an organic solvent, and then adding a chlorination reagent to react to obtain a compound IV shown in the following formula;
(2) under the catalysis of alkali, reacting the compound IV obtained in the step (1) with phenol to obtain a compound III shown in the following formula;
(3) placing the compound III obtained in the step (2) in an organic solvent, and carrying out Fries rearrangement reaction to obtain a compound II;
(4) performing alkylation reaction on the compound II obtained in the step (3) and bromoethane or iodoethane to obtain a compound I with the following formula, wherein the compound I is a target product 5-bromo-2-chloro-2' -ethoxy benzophenone,
wherein, X is chlorine or bromine.
2. The method of preparing dapagliflozin impurity according to claim 1, characterized in that: the reaction temperature of the chlorination reaction in the step (1) is 30-80 ℃, and the reaction time is 3-5 h.
3. The method of preparing dapagliflozin impurity according to claim 1, characterized in that: the chlorination reagent in the step (1) is one of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride, and the mass ratio of the chlorination reagent to the compound V is (2-4): 1.
4. The method of preparing dapagliflozin isomer impurity according to claim 1, characterized in that: in the step (2), the base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and N, N-diisopropylethylamine, and the mass ratio of the base to the compound V is (1-5): 1.
5. The method of preparing dapagliflozin isomer impurity according to claim 1, characterized in that: in the step (2), the mass ratio of the phenol to the compound V is (2-5): 1.
6. The process for the preparation of dapagliflozin isomer impurity i according to claim 1, characterized in that: the rearrangement reaction in the step (3) is carried out in the presence of a catalyst, the catalyst is one of aluminum trichloride, zinc chloride and trifluoroacetic anhydride, the temperature of the rearrangement reaction is 120-200 ℃, and the reaction time is 5-7 h.
7. The method of preparing dapagliflozin isomer impurity according to claim 1, characterized in that: the organic solvent for the rearrangement reaction in the step (3) is one of chlorobenzene, nitrobenzene and 1,1,2, 2-tetrachloroethane.
8. The method of preparing dapagliflozin impurity according to claim 1, characterized in that: the molar ratio of bromoethane or iodoethane used in the alkylation reaction in the step (4) to the compound of the formula III is (1.5-3.5): 1.0.
9. The method of preparing dapagliflozin impurity according to claim 1, characterized in that: in the step (4), the alkylation reaction is carried out in one of solvents of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, 1, 4-dioxane, tetrahydrofuran and acetonitrile.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115417836A (en) * | 2022-09-21 | 2022-12-02 | 安庆奇创药业有限公司 | Method for synthesizing lean hypoglycemic drug intermediate by using continuous flow |
| CN116041152A (en) * | 2023-02-08 | 2023-05-02 | 河南立诺制药有限公司 | Preparation method of dapagliflozin brominated side chain isomer impurity |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| EUN MI KWON,等: "Preparation of Benzoyloxy Benzophenone Derivatives and Their Inhibitory Effects of ICAM-1 Expression", BULL. KOREAN CHEM. SOC., vol. 33, no. 6, pages 1939 - 1944 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115417836A (en) * | 2022-09-21 | 2022-12-02 | 安庆奇创药业有限公司 | Method for synthesizing lean hypoglycemic drug intermediate by using continuous flow |
| CN116041152A (en) * | 2023-02-08 | 2023-05-02 | 河南立诺制药有限公司 | Preparation method of dapagliflozin brominated side chain isomer impurity |
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