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Synthesizing method suitable for industrial empagliflozin production

A synthetic method, the technology of empagliflozin, applied in the field of industrial production of empagliflozin, can solve the problems of difficult refining and purification of intermediates, cumbersome operation, high process cost, etc., achieve strong practical application value and improve product quality , reduce the effect of high toxicity

Pending Publication Date: 2019-10-08
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Method 1: The preparation method of Empagliflozin in patent CN102574829B involves many reduction reactions, and there are two-step reactions that require the use of aluminum trichloride and a reducing agent. Not only is the operation cumbersome, but also a large amount of waste acid is produced, and the post-treatment is complicated; In addition, the above-mentioned reduction reaction should be carried out under strict anhydrous conditions. The presence of moisture will lead to more by-product impurities under acidic conditions, and the total yield of empagliflozin is low; therefore, this preparation method is not suitable for industrial production.
[0011] Method 2: The preparation method in the patent CN101193903B has a long route, high process cost, and also has many reduction reactions, requiring repeated use of Lewis acid and reducing agent, and the refining and purification of intermediates is difficult, and quality control cannot be carried out during the preparation process , the total yield of Empagliflozin is low, so it is not suitable for industrial production

Method used

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  • Synthesizing method suitable for industrial empagliflozin production
  • Synthesizing method suitable for industrial empagliflozin production
  • Synthesizing method suitable for industrial empagliflozin production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Step (1): Preparation of compound (III-1)

[0043] Add 117 g of compound (IV-1) and a mixed solvent of toluene / tetrahydrofuran (volume ratio 2:1, total volume 700 mL) into a four-neck flask, stir and mix evenly. Under the protection of nitrogen, the internal temperature of the system was lowered to -80° C., and then 93 g of a 2.5 M n-butyllithium solution in n-hexane was added dropwise. After the addition was completed, 300 g of compound (V-1) in toluene was added dropwise after stirring for 20 minutes (150 g of compound (V-1) was diluted with an equal amount of toluene). After the addition, keep stirring for 2 hours. Continue to dropwise add methanesulfonic acid / methanol mixed solution (59g / 230g). After the addition was complete, the temperature of the system was raised to 30°C and the reaction was stirred for 12 hours. After the reaction was finished, the reaction solution was added to 500ml of saturated aqueous sodium bicarbonate solution to quench, and then 1000m...

Embodiment 2

[0051] Step (1): Preparation of compound (III-1)

[0052] Add 8.0Kg of compound (IV-1) and a mixed solvent of toluene / tetrahydrofuran (volume ratio 2:1, total volume 48.0L) into a 200L ultra-low temperature reactor, stir and mix well. Under the protection of nitrogen, the internal temperature of the system was lowered to -80°C, and then 6.4Kg of 2.5M n-butyl lithium in n-hexane was added dropwise. After the addition was completed, 20.6 kg of compound (V-1) in toluene was added dropwise after stirring for 30 minutes (10.3 kg of compound (V-1) was diluted with an equal amount of toluene). After the addition, keep stirring for 2 hours. Continue to drop methanesulfonic acid / methanol mixed solution (4.0Kg / 15.7Kg). After the addition was complete, the temperature of the system was raised to 30°C and the reaction was stirred for 12 hours. After the reaction was completed, the reaction solution was added to 34.2Kg saturated aqueous sodium bicarbonate solution to quench, and then 54...

Embodiment 3

[0060] Step (1): Preparation of compound (III-1)

[0061] Add 20.0Kg of compound (IV-1) and a mixed solvent of toluene / tetrahydrofuran (volume ratio 2:1, total volume about 120L) into a 500L ultra-low temperature reactor, stir and mix well. Under the protection of nitrogen, the internal temperature of the system was lowered to -80°C, and then 15.9Kg of 2.5M n-butyl lithium in n-hexane was added dropwise. After the addition was completed, 51.2 kg of compound (V-1) in toluene was added dropwise after stirring for 30 minutes (25.6 kg of compound (V-1) was diluted with an equal amount of toluene). After the addition, keep stirring for 2 hours. Continue to drop methanesulfonic acid / methanol mixed solution (10.0Kg / 39.3Kg). After the addition was complete, the temperature of the system was raised to 30°C and the reaction was stirred for 12 hours. After the reaction, the reaction solution was added to 85.5Kg saturated aqueous sodium bicarbonate solution to quench, then 140Kg ethyl ...

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Abstract

The invention discloses a synthesizing method suitable for industrial empagliflozin production. The synthesizing method includes: subjecting a compound as shown in formula (II) to reduction reaction to obtain a compound as shown in formula (I), and removing the protecting groups of the compound as shown in formula (I) to obtain empagliflozin. The synthesizing method has the advantages that the method is simple in process, only needs one-step reduction reaction and can effectively reduce the repeated use of high-toxicity and high-risk chemicals; in addition, the intermediate purified after derivation protection, effective process control is achieved, and product quality is increased; the method is high in practical application value and suitable for industrial production.

Description

technical field [0001] The invention relates to a drug synthesis method, in particular to a synthesis method suitable for industrial production of empagliflozin. Background technique [0002] Empagliflozin, molecular formula: C 23 h 27 ClO 7 , chemical name: (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furyl]oxy]phenyl]methanol Base] phenyl] -D-glucitol. Empagliflozin was approved for marketing by the US FDA in August 2014. It was jointly developed by two well-known pharmaceutical companies, Eli Lilly and Boehringer Ingelheim. The glucose content of , which is mainly used in the treatment of adults with type 2 diabetes, has the structural formula: [0003] [0004] Empagliflozin existing synthesis method: [0005] Synthetic method one: CN102574829B reports a method for synthesizing empagliflozin: [0006] (3S )-3-[4-[(5-iodo-2-chlorophenyl)methyl]phenoxy]tetrahydrofuran, Grignard reaction with 2,3,4,6-tetra-O-trimethylsilyl- D-gluconolactone is conden...

Claims

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Application Information

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IPC IPC(8): C07D407/12
CPCC07D407/12Y02P20/55
Inventor 骆伟辜天彬杨成喜王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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