Preparation method of ertugliflozin intermediate
Through a new preparation method, the hydroxymethyl group at 6 is protected and the hydroxymethyl group at 3, 4 and 5 are protected in the presence of a base, and then react with 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene, the complex problem of protecting group conversion in the prior art is solved, and the efficient preparation of ergliflozin intermediates is achieved.
Patent Information
- Application Number
- CN202411638720.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-06
- Publication Date
- 2025-02-25
AI Technical Summary
In the existing preparation method for ergliflozin intermediates, the conversion of protecting groups extends the reaction step and increases the production cost.
Using a new preparation method, the synthesis of the egliflozin intermediate was completed by protecting the hydroxymethyl group at 6, followed by reaction in the presence of a base to protect the hydroxyl groups at 3, 4 and 5, followed by reaction with 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene, and the synthesis of the egliflozin intermediate was completed in the presence of an acid.
It effectively improves the reaction efficiency, simplifies the protection group conversion step, and reduces production costs.
Smart Images
Figure CN119504899A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of pharmaceutical chemical industry, and designs a method for preparing an intermediate of ergliflozin, a SGLT-2 inhibitor for treating diabetes. Background Art
[0002] Egliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor, mainly used to treat type 2 diabetes (T2D). SGLT2 inhibitors inhibit the function of SGLT2 in the kidneys and reduce the reabsorption of glucose in the primary urine, thereby helping diabetic patients lower their blood sugar levels. Compound 5 is an intermediate of Egliflozin, used in the synthesis of Egliflozin API. The chemical structure of the Egliflozin intermediate is shown below:
[0003]
[0004] At present, the preparation method of ergliflozin intermediate disclosed in the literature uses gluconolactone as a raw material, and its synthesis route is as follows:
[0005]
[0006] The existing route mainly has the following problems: trimethylsilyl (TMS) is first used to protect the hydroxyl group, and then it is replaced with a benzyl protecting group. The conversion of the protecting group not only prolongs the reaction steps but also increases the production cost. Summary of the invention
[0007] In order to overcome the deficiencies of the prior art, the present invention provides a new method for preparing an ergliflozin intermediate, which can effectively improve the reaction efficiency.
[0008] The technical solution adopted by the present invention is: a method for preparing an ergliflozin intermediate, comprising the following steps:
[0009] Step 1: Using (3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-hydroxymethyltetrahydro-2H-pyran-2-one (Compound 1) as the starting material, adding a protective agent at low temperature, and protecting the 6-hydroxymethyl group to obtain Compound 2 as shown in Formula (I):
[0010]
[0011] Step 2: Compound 2 is reacted in the presence of a base at 0-25°C, and the hydroxyl groups at positions 3, 4, and 5 are protected with a benzyl group to obtain a compound 3 having a structure as shown in formula (II):
[0012]
[0013] Step 3: Compound 3 is reacted with 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene in the presence of a base at -100 to 0°C, and treated with a methanesulfonic acid / methanol solution to obtain compound 4 having a structure as shown in formula (III).
[0014]
[0015] Step 4: Compound 4 is reacted in the presence of an acid at -0 to 25°C to obtain an ergliflozin intermediate (compound 5) having a structure as shown in formula (IV).
[0016]
[0017] Its synthetic route is:
[0018]
[0019] In the present invention, the preparation method of compound 2 preferably adopts the following reaction conditions:
[0020] The raw material used is (3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-hydroxymethyltetrahydro-2H-pyran-2-one;
[0021] The solvent used is one or any combination of two or more of acetonitrile, dimethyl sulfoxide, dichloromethane, anhydrous ethanol or tetrahydrofuran;
[0022] The base used is selected from any one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine and pyridine;
[0023] The protective agent used was tert-butyldiphenylchlorosilane (TBDPSCl);
[0024] The molar ratio of the raw materials used is (3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-hydroxymethyltetrahydro-2H-pyran-2-one:TBDPSCl:base=1:1.1-1.5:2.0-3.0;
[0025] The reaction temperature is -20 to 10°C;
[0026] The reaction time is 6 to 12 hours;
[0027] In the present invention, the preparation method of compound 3 preferably adopts the following reaction conditions:
[0028] The raw material used was compound 2;
[0029] The solvent used is one or any combination of two or more of dimethylformamide, dichloromethane, benzene, toluene, acetonitrile, 1,4-dioxane or tetrahydrofuran;
[0030] The base used is any one of sodium hydride, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, and pyridine;
[0031] The protective agent used was benzyl bromide;
[0032] The molar ratio of the raw materials used is: compound 2: base: benzyl bromide = 1.0: 3.0-5.0: 3.0-4.0;
[0033] The reaction temperature is 0-25°C;
[0034] The reaction time is 6 to 12 hours;
[0035] In the present invention, the preparation method of compound 4 preferably adopts the following reaction conditions:
[0036] The raw material used was compound 3;
[0037] The solvent used is one or any combination of two or more of benzene, toluene, 1,4-dioxane, N,N-dimethylformamide, or tetrahydrofuran;
[0038] The base used is any one of methyl lithium, tert-butyl lithium, lithium aluminum hydride, and n-butyl lithium;
[0039] The molar ratio of the raw materials used is: compound 3: base: 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene = 1: 1.1-1.5: 1.1-1.5;
[0040] The reaction temperature is -100~0℃;
[0041] The reaction time is 3 to 6 hours;
[0042] In the present invention, the method for preparing the ergliflozin intermediate preferably adopts the following reaction conditions:
[0043] The raw material used was compound 4;
[0044] The solvent used is one or any combination of two or more of dichloromethane, chloroform, ethyl acetate, toluene, acetonitrile, dimethyl sulfoxide, 1,4-dioxane or tetrahydrofuran;
[0045] The acid used is any one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrobromic acid, hydroiodic acid, and methanesulfonic acid;
[0046] The molar ratio of the raw materials used is compound 4: acid = 1: 2.0-5.0;
[0047] The reaction temperature is 0-25°C;
[0048] The reaction time is 2 to 6 hours; DETAILED DESCRIPTION
[0049] The technical solution of the present invention is further described below to enable those skilled in the art to further understand the present invention, but does not constitute a limitation on the rights of the present invention.
[0050] Example 1 The implementation method of the ergliflozin intermediate in this example comprises the following steps:
[0051]
[0052] 1) The preparation method of compound 2 is as follows: compound 1 (1.0 g, 5.6 mmol) is weighed and dissolved in tetrahydrofuran (30.0 ml), triethylamine (2.5 ml, 12.8 mmol) and tert-butyldiphenylsilyl chloride (1.7 g, 6.2 mmol) are added in sequence, the mixture is stirred at -10°C for 2 hours, and then reacted at 25°C for 4 hours. After the reaction is completed by TLC monitoring, the mixture is washed with water, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 2.
[0053]
[0054] 2) The preparation method of compound 3 is as follows: Compound 2 (2.8 g, 6.6 mmol) is added to a reaction bottle and dissolved in tetrahydrofuran (10.0 ml). Sodium hydroxide (0.8 g, 20.0 mmol) and benzyl bromide (2.3 ml, 19.8 mmol) are added to the solution in sequence, and the mixture is heated to 80°C for reaction. After the reaction is completed by TLC monitoring, water is added to quench the mixture, the mixture is extracted with DCM, dried over anhydrous sodium sulfate, the solvent is dried by spin drying, and compound 3 is obtained by purification by column chromatography.
[0055]
[0056] 3) The preparation method of compound 4 is as follows: 5-bromo-2-chloro-4′-ethoxydiphenylmethane (0.5 g, 1.8 mmol) was weighed and dissolved in tetrahydrofuran (30.0 ml). Under nitrogen protection, n-butyl lithium (1.8 ml, 1.8 mmol) was slowly dropped into the solution. After 10 minutes, compound 3 (1.0 g, 1.5 mmol) was added. The mixture was stirred at -70°C for 3 hours. After the reaction was completed by TLC monitoring, compound 4 was obtained by washing with water, extraction and drying.
[0057]
[0058] 4) The implementation method of the ergliflozin intermediate is as follows: Compound 4 (1.0 g, 1.1 mmol) is dissolved in tetrahydrofuran (10.0 ml), and then methanesulfonic acid (0.1 ml, 1.6 mmol) is added. The reaction temperature is 25°C, and the reaction is carried out for 4 hours. After the reaction is completed by TLC monitoring, NaOH solution is added for neutralization, the phases are separated, the aqueous phase is extracted with toluene, and the organic phases are combined; the phases are washed once with saturated brine, and the phases are concentrated under reduced pressure to obtain the ergliflozin intermediate (compound 5).
[0059] Example 2 The implementation method of the ergliflozin intermediate of this example comprises the following steps:
[0060]
[0061] 1) The preparation method of compound 2 is as follows: weigh compound 1 (10.0 g, 56.0 mmol) and dissolve it in acetonitrile (40.0 ml), add sodium hydroxide (4.5 g, 112.5 mmol) and tert-butyldiphenylsilyl chloride (18.5 g, 67.0 mmol) in sequence, keep the reaction stirring at 0°C for 6 hours, and after the reaction is completed by TLC monitoring, extract with ethyl acetate to obtain compound 2.
[0062]
[0063] 2) The preparation method of compound 3 is as follows: Compound 2 (10.0 g, 24.0 mmol) is added to a reaction bottle and dissolved in acetonitrile (60.0 ml). Triethylamine (10.0 ml, 72.0 mmol) and benzyl bromide (8.5 ml, 72.0 mmol) are added to the solution in sequence, and the mixture is heated to 60° C. under nitrogen protection for reaction. After the reaction is completed by TLC monitoring, saturated brine is added for quenching, and the mixture is extracted with ethyl acetate and purified by column chromatography to obtain compound 3.
[0064]
[0065] 3) The preparation method of compound 4 is as follows: 5-bromo-2-chloro-4′-ethoxydiphenylmethane (5.2 g, 16.0 mmol) was weighed and dissolved in toluene (30.0 ml). Under nitrogen protection, tert-butyl lithium (18.0 ml, 18.0 mmol) was slowly dropped into the solution. After 10 minutes, compound 3 (10.0 g, 14.0 mmol) was weighed. The reaction mixture was stirred at -20°C for 6 hours. After the reaction was completed by TLC monitoring, the product 4 was obtained by extraction with water, extraction with ethyl acetate and drying over anhydrous sodium sulfate.
[0066]
[0067] 4) The implementation method of the ergliflozin intermediate is:
[0068] The preparation method of the ergliflozin intermediate is as follows: compound 4 (10.0 g, 10.6 mmol) is dissolved in acetonitrile (50.0 ml), and then concentrated sulfuric acid (2.0 ml, 24.0 mmol) is added, the reaction temperature is 0°C, the reaction is carried out for 3 hours, the reaction is dried by rotary evaporation, and the ergliflozin intermediate (compound 5) is obtained after column chromatography.
Claims
1. A method for preparing an ergliflozin intermediate, characterized in that The steps include: Step 1: Using (3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-hydroxymethyltetrahydro-2H-pyran-2-one (Compound 1) as a raw material, the 6-hydroxymethyl group is protected under alkaline conditions to obtain Compound 2 having a structure as shown in Formula (I). Step 2: Using compound 2 as a raw material, the hydroxyl groups at positions 3, 4, and 5 are protected with benzyl groups under alkaline conditions to obtain compound 3 having a structure as shown in formula (II). Step 3: Compound 3 is coupled with 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene under the action of a base, and then acidified in a methanesulfonic acid / methanol solution to obtain compound 4 having a structure as shown in formula (III). Step 4: Using compound 4 as a raw material, the protective group of the 6-hydroxymethyl group is removed in the presence of an acid to obtain an ergliflozin intermediate (compound 5) having a structure as shown in formula (IV).
2. The method for synthesizing compound 2 according to claim 1, characterized in that: The solvent used in step 1 is selected from one or any combination of acetonitrile, dimethyl sulfoxide, dichloromethane, anhydrous ethanol or tetrahydrofuran. The base used is selected from any one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine and pyridine. The reaction temperature is -20 to 10°C.
3. The method for synthesizing compound 3 according to claim 1, characterized in that: The solvent used in step 2 is selected from one or any combination of dimethylformamide, dichloromethane, benzene, toluene, acetonitrile, 1,4-dioxane or tetrahydrofuran. The base used is selected from any one of sodium hydride, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and pyridine. The reaction temperature is 0 to 25°C.
4. The method for synthesizing compound 4 according to claim 1, characterized in that The solvent used in step 3 is selected from one or any combination of benzene, toluene, 1,4-dioxane, N,N-dimethylformamide, or tetrahydrofuran. The base is selected from any one of methyl lithium, tert-butyl lithium, lithium aluminum hydride, and n-butyl lithium. The reaction temperature is -100 to 0°C.
5. The method for synthesizing the ergliflozin intermediate (Compound 5) according to claim 1, characterized in that The solvent used in step 4 is selected from one or any combination of dichloromethane, chloroform, ethyl acetate, toluene, acetonitrile, dimethyl sulfoxide, 1,4-dioxane or tetrahydrofuran. The reaction temperature is 0 to 25° C. The acid used is selected from any one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid and p-toluenesulfonic acid.