Preparation method of etogliflozin intermediate
By using an imidazole and trimethylchlorosilane reaction system in the synthesis of eletogliflozin, the 6-hydroxyl protecting group of compound V is removed with high selectivity, solving the problems of poor selectivity and frequent solvent switching in the prior art, improving product quality and yield, and making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
- Filing Date
- 2026-01-29
- Publication Date
- 2026-05-12
AI Technical Summary
In the existing synthetic route of eletogliflozin, the selective removal of the 6-hydroxyl protecting group from compound V to compound VI suffers from poor selectivity and excessive feed residue, which affects product quality and yield. Furthermore, the existing method requires multiple solvent conversions, increasing cost and time.
Using imidazole as a base in an organic solvent, after reacting with trimethylchlorosilane, a small amount of water and methanol are added. The 6-hydroxyl protecting group is removed with high selectivity through temperature-controlled reaction, simplifying the operation steps and reducing impurities.
It achieves highly selective preparation of compound VI, reduces impurities, improves product yield, simplifies the operation process, and is suitable for large-scale production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a method for preparing an intermediate of atorvagliflozin. Background Technology
[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia, caused by absolute or relative insulin deficiency and impaired insulin utilization. Type 2 diabetes is the most common form. In recent years, SGLT-2 inhibitors such as etoragliflozin have provided new insights into the treatment of type 2 diabetes. SGLT-2 inhibitors inhibit the reabsorption of glucose by the kidneys, causing excess glucose to be excreted in the urine, thereby lowering blood sugar levels.
[0003] Ertugliflozin, chemically named (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol and (2S)-5-pyrrolidone-2-carboxylic acid, was jointly developed by Pfizer and Merck and was approved for marketing in China on July 30, 2020, under the trade name Genodextrin. Its structural formula is as follows:
[0004] .
[0005] There are currently several routes for synthesizing eltogliflozin, but the mainstream route uses 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (Formula II) and 5-bromo-2-chloro-4′-ethoxydiphenylmethane (Formula III) as starting materials. These are coupled under the action of n-butyllithium to obtain compound IV. Then, the hydroxyl group is protected with a trimethylsilyl group to obtain compound V. Compound V is then selectively deprotected at the 6-position to obtain compound VI. Subsequently, eltogliflozin is obtained through Parikh-Doering oxidation, a cross-linked Crossed-Cannizzaro reaction, and an acid-catalyzed etherification cyclization reaction. Finally, it is co-crystallized with L-pyroglutamic acid to obtain the eltogliflozin active pharmaceutical ingredient. The synthetic route is as follows:
[0006]
[0007] The starting materials for this route are readily available and inexpensive, and the reaction operation is simple, making it suitable for industrial production. However, when selectively removing the protecting group at the 6-position hydroxyl group from compound V to compound VI, the current process suffers from problems such as poor selectivity or excessive residual raw materials.
[0008] Patent CN10214917B uses a 1% potassium carbonate methanol solution for selective removal. This method involves multiple solvent conversions: first, the dichloromethane solution of compound V must be converted to methanol; after the potassium carbonate reaction, it must be converted back to dichloromethane for the next reaction. With large batches, this prolongs the operation time, causes some protecting groups to detach, increases impurities, and consequently affects the quality of subsequent product steps. Furthermore, the multiple solvent conversions increase costs and extend processing time, making it unsuitable for industrial production.
[0009] The literature Org. Process Res. Dev. 2014, 18 (1), 57~65 uses a mixed aqueous solution of p-toluenesulfonic acid and pyridine (PPTs) for selective deprotection. This method does not require solvent conversion and has fewer impurities, but it leaves 8% of compound V as a residue. Compound V is deprotected and converted to compound IV in subsequent processes, which is removed by multiple recrystallizations, greatly affecting the product yield. Summary of the Invention
[0010] To address the shortcomings of existing technologies, this invention provides a method for preparing an etoragliflozin intermediate. To achieve the above objective, this invention adopts the following technical solution:
[0011] (1) Compound IV reacts with trimethylchlorosilane under organic solvent and alkaline conditions to give compound V;
[0012] (2) Add a small amount of water and a certain amount of methanol to step (1) and heat the reaction. After the reaction is complete, prepare compound VI after post-treatment.
[0013] Its synthetic route is as follows:
[0014]
[0015] Preferably, in step (1), the organic solvent is dichloromethane and the base is imidazole.
[0016] Preferably, the molar ratio of compound IV, base and trimethylchlorosilane in step (1) is 1:5~8:5~8; more preferably, the molar ratio of compound IV, base and trimethylchlorosilane is 1:6~6.5:6.
[0017] Preferably, in step (1), the volume-to-mass ratio of the organic solvent to compound IV is 8-10 ml / g.
[0018] Preferably, the volume ratio of methanol to organic solvent in step (1) in step (2) is 1:1 to 4; more preferably, it is 1:1 to 2.
[0019] Preferably, the reaction temperature in step (2) is 30~43℃; more preferably, the reaction temperature is 40℃.
[0020] Preferably, the reaction time in step (2) is 4 to 8 hours, and more preferably, the reaction time is 6 hours.
[0021] Preferably, the post-treatment involves cooling, adding water to dissolve the compound, and then drying with anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI.
[0022] The beneficial effects of this invention are:
[0023] (1) The reaction of the present invention is a continuous feeding process. The appropriate amount of imidazole hydrochloride generated in step (1) is then added to methanol to achieve the effect of highly selective removal of the 6-position hydroxyl protecting group. The operation steps are few, the reaction conditions are simple and controllable, and it is suitable for large-scale production.
[0024] (2) The present invention has good selectivity in the deprotection reaction and fewer impurities in the preparation of compound VI; the reaction conversion rate is high and the residual amount of compound VI raw material is low, which reduces the purification pressure of subsequent steps and improves the product yield. Detailed Implementation
[0025] Example 1
[0026] 30g of compound IV was dissolved in 240ml of dichloromethane, followed by 27.9g (6.0 equivalents) of imidazole. 44.6g (6.0 equivalents) of trimethylchlorosilane was added dropwise at 20-25℃. After the addition was complete, the reaction was allowed to proceed for 1 hour. Excess trimethylchlorosilane was quenched with 3g of water, then dissolved in 120ml of methanol. The mixture was heated to 40℃ and refluxed for 6 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and 240ml of purified water was added. The mixture was separated, and the lower organic phase was dried over 15g of anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI. HPLC analysis showed a purity of 97.4%, with 1.2% of compound IV remaining.
[0027] Example 2
[0028] 30g of compound IV was dissolved in 240ml of dichloromethane, followed by the addition of 30.2g (6.5 equivalents) of imidazole. 44.6g (6.0 equivalents) of trimethylchlorosilane was added dropwise at 20-25℃. After the addition was complete, the reaction was allowed to proceed for 1 hour. Excess trimethylchlorosilane was quenched with 3g of water, followed by the addition of 120ml of methanol. The mixture was then refluxed at 40℃ for 6 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and 240ml of purified water was added. The mixture was separated, and the lower organic phase was dried over 15g of anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI. HPLC analysis showed a purity of 97.9%, with 0.6% of compound IV remaining.
[0029] Example 3
[0030] 30g of compound IV was dissolved in 300ml of dichloromethane, followed by the addition of 30.2g (6.5 equivalents) of imidazole. 44.6g (6.0 equivalents) of trimethylchlorosilane was added dropwise at 20-25℃. After the addition was complete, the reaction was allowed to proceed for 1 hour. Excess trimethylchlorosilane was quenched with 3g of water, and then dissolved in 300ml of methanol. The mixture was then heated to 43℃ and refluxed for 6 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and 240ml of purified water was added. The mixture was separated, and the lower organic phase was dried over 15g of anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI. HPLC analysis showed a purity of 98.0%, with 0.6% of compound IV remaining.
[0031] Example 4
[0032] 30g of compound IV was dissolved in 300ml of dichloromethane, followed by the addition of 30.2g (6.5 equivalents) of imidazole. 44.6g (6.0 equivalents) of trimethylchlorosilane was added dropwise at a controlled temperature of 20-25℃. After the addition was complete, the reaction was allowed to proceed for 1 hour. Excess trimethylchlorosilane was quenched with 3g of water, and then dissolved in 300ml of methanol. The temperature was raised to 30℃ and the reaction was allowed to proceed for 8 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and 240ml of purified water was added. The mixture was separated, and the lower organic phase was dried over 15g of anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI. HPLC analysis showed a purity of 97.0%, with 1.5% of compound IV remaining.
[0033] Example 5
[0034] 30g of compound IV was dissolved in 240ml of dichloromethane, followed by 23.3g (5.0 equivalents) of imidazole. 37.2g (5.0 equivalents) of trimethylchlorosilane was added dropwise at 20-25℃. After the addition was complete, the reaction was allowed to proceed for 1 hour. Excess trimethylchlorosilane was quenched with 3g of water, then dissolved in 120ml of methanol. The temperature was raised to 40℃ and the reaction was allowed to proceed for 8 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and 240ml of purified water was added. The mixture was separated, and the lower organic phase was dried over 15g of anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI. HPLC analysis showed a purity of 96.5%, with 1.9% of compound IV remaining.
[0035] Example 6
[0036] 30g of compound IV was dissolved in 300ml of dichloromethane, followed by the addition of 37.2g (8.0 equivalents) of imidazole. 59.5g (8.0 equivalents) of trimethylchlorosilane was added dropwise at a controlled temperature of 20-25℃. After the addition was complete, the reaction was allowed to proceed for 1 hour. Excess trimethylchlorosilane was quenched with 5g of water, and then dissolved in 300ml of methanol. The temperature was raised to 40℃ and the reaction was allowed to proceed for 8 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and 240ml of purified water was added. The mixture was separated, and the lower organic phase was dried over 15g of anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI. HPLC analysis showed a purity of 96.8%, with 1.6% of compound IV remaining.
Claims
1. A method for preparing an atorpagliflozin intermediate, characterized in that, The preparation method includes the following steps: (1) Compound IV reacts with trimethylchlorosilane under organic solvent and alkaline conditions to give compound V; (2) Add a small amount of water and a certain amount of methanol to step (1) and heat the reaction. After the reaction is complete, prepare compound VI after post-treatment. Its synthetic route is as follows: 。 2. The method for preparing the eletogliflozin intermediate according to claim 1, characterized in that, In step (1), the organic solvent is dichloromethane and the base is imidazole.
3. The method for preparing the eletogliflozin intermediate according to claim 1, characterized in that, In step (1), the molar ratio of compound IV, base and trimethylchlorosilane is 1:5~8:5~8; preferably 1:6~6.5:
6.
4. The method for preparing the eletogliflozin intermediate according to claim 1, characterized in that, In step (1), the volume-to-mass ratio of the organic solvent to compound IV is 8-10 ml / g.
5. The method for preparing the eletogliflozin intermediate according to claim 1, characterized in that, In step (2), the volume ratio of methanol to organic solvent in step (1) is 1:1 to 4, preferably 1:1 to 2.
6. The method for preparing the eletogliflozin intermediate according to claim 1, characterized in that, The reaction temperature in step (2) is 30~43℃, preferably 40℃.
7. The method for preparing the eletogliflozin intermediate according to claim 1, characterized in that, The reaction time for step (2) is 4 to 8 hours, preferably 6 hours.
8. The method for preparing the eletogliflozin intermediate according to claim 1, characterized in that, The post-treatment involves cooling, adding water to dissolve the compound, and then drying with anhydrous sodium sulfate to obtain a dichloromethane solution of compound VI.