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CN-122017111-A - Reversed phase chromatography method for measuring content of related substances and enantiomer of Engliflozin intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran

CN122017111ACN 122017111 ACN122017111 ACN 122017111ACN-122017111-A

Abstract

The invention provides a method for simultaneously detecting related substances and enantiomer contents of an englitazone intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran by using a reversed phase chromatography, and relates to the technical field of analytical chemistry. The method provided by the invention has good specificity, high sensitivity and short operation time, can accurately detect specific impurities such as related substances (S) - (5-bromo-2-chlorophenyl) [4- [ (tetrahydrofuran-3-yl) oxy ] phenyl ] methanone (EP 5), (5-bromo-2-chlorophenyl) [4- [ (S) -tetrahydrofuran-3-yl) oxy ] phenyl ] methanol (EP 4A), 1, 4-bis [4- (5-bromo-2-chlorobenzyl) phenoxy ] butane (EP 4K) and enantiomer (R) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran (EP 4B) in the enggliflozin intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran, and has the maximum unknown impurity and total impurity content.

Inventors

  • ZHU ZHENXING
  • Ma Mirong
  • YU ANSHENG
  • YAN JIANBO
  • SUN MEILING
  • YANG FAN

Assignees

  • 浙江宏元药业股份有限公司

Dates

Publication Date
20260512
Application Date
20260109

Claims (6)

  1. 1. A method for detecting the content of an englitant intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran and an enantiomer by reverse phase chromatography, comprising: Mixing an EP4 test sample with an organic solvent to obtain a test sample solution, and detecting the test sample solution by a high performance liquid chromatography, wherein the high performance liquid chromatography column is a polysaccharide derivative bonding type filler chiral chromatography column, and the mobile phase consists of acetonitrile and purified water and adopts gradient elution.
  2. 2. The method according to claim 1, wherein the high performance liquid chromatography is performed by gradient elution. Mobile phase a is purified water, mobile phase B is acetonitrile, preferably with a gradient of: 0-5 min,55% A, 5-25 min, 55%. Fwdarw.30% A, 25-40 min, 30%. Fwdarw. 15% A, 40-52 min,15% A, 52-52.1 min,15% -55% A, 52.1-60 min,55% A.
  3. 3. The method according to claim 1, wherein the flow rate is 0.8-1.2 mL min -1 , preferably 1.0mL min -1 , during the detection by high performance liquid chromatography.
  4. 4. The method of claim 1, wherein the chromatographic column is a polysaccharide derivative-bonded chiral packing as a filler, preferably CHIRAL PAK ® IC.
  5. 5. The method according to claim 1, wherein the high performance liquid chromatography column temperature is 25-35 ℃ and the sample injection volume is 5-15 μl.
  6. 6. The detection method according to claim 1, wherein the detection wavelength by high performance liquid chromatography is 210-230 nm.

Description

Reversed phase chromatography method for measuring content of related substances and enantiomer of Engliflozin intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran Technical Field The invention belongs to the technical field of analytical chemistry, and relates to a detection method of an englitazone intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran related substance and enantiomer. More specifically, the invention relates to a detection method of an englitant intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran related substance (EP 4A, EP, EP 4K) and enantiomer (EP 4B). Background Engliflozin is a sodium-glucose cotransporter 2 (SGLT 2) inhibitor developed by Boringer's invar in combination with Gift for the treatment of type 2 diabetes, adult chronic heart failure and adult chronic kidney disease patients. The approval of FDA for clinical use in 2014, 8 months in 2017, englitjing was first approved in china for the treatment of T2 DM. 2022. For 6 months, engagliflozin was approved in china for the treatment of adult patients with heart failure with or without diabetes mellitus, with reduced ejection fraction. 2023. For 5 months of the year, engagliflozin was approved in china for combination insulin therapy (with or without oral hypoglycemic agents) to improve glycemic control in type 2 diabetics on a dietary and exercise basis. 2023. Engliflozin, china, was approved for the treatment of adult Chronic Kidney Disease (CKD) for 11 months. CKD, heart failure, type 2 diabetes, and the like, have an impact on more than 10 billion people worldwide. Engliflozin is the only oral hypoglycemic agent in the first ten of the top half of 2025 years. The national drug administration website displays that the number of the single and compound approval clerks in the Engliflozin of the current Chinese market reaches 89, and the manufacturers are 49. PCT patent W02006120208A 7 reports a main process route of the prior Engliflozin bulk drug, wherein the main process route comprises a key intermediate (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran, as shown in formula EP4, and the preparation method comprises the steps of taking 5-bromo-2-chlorobenzoic acid as a starting material, condensing with (S) -3-hydroxytetrahydrofuran after Friedel-crafts reaction, and finally reducing. The EP4 potential impurity and process impurity comprise a potential impurity enantiomer (R) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran which is introduced by a raw material and is shown as a formula EP4B, a dimer impurity 1, 4-bis [4- (5-bromo-2-chlorobenzyl) phenoxy ] butane which is shown as a formula EP4K, a process impurity (5-bromo-2-chlorophenyl) [4- [ (S) -tetrahydrofuran-3-yl) oxy ] phenyl ] methanol which is shown as a formula EP4A, and a former step intermediate residue (S) - (5-bromo-2-chlorophenyl) [4- [ (tetrahydrofuran-3-yl) oxy ] phenyl ] methanone which is shown as a formula EP 5. EP4 contains Guan Zazhi (EP 4A, EP5 and EP 4K) and enantiomer impurities (EP 4B) which are synthesized and transferred to the Engliflozin bulk drug through a chemical process to generate specific impurities such as Engliflozin enantiomer, engliflozin dimer impurities and the like, and the standard of the specific impurities in the bulk drug is less than or equal to 0.15 percent, so that a suitable analysis method of the EP4 related impurities and the EP4 enantiomer is established, reference is provided for controlling the EP4 impurities, and the quality of the Engliflozin bulk drug is ensured to have important significance. (S) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran (EP 4) (5-Bromo-2-chlorophenyl) [4- [ (S) -tetrahydrofuran-3-yl) oxy ] phenyl ] methanol (EP 4A) (R) -3- [4- (5-bromo-2-chlorobenzyl) phenoxy ] tetrahydrofuran (EPB) (S) - (5-bromo-2-chlorophenyl) [4- [ (tetrahydrofuran-3-yl) oxy ] phenyl ] methanone (EP 5) 1, 4-Bis [4- (5-bromo-2-chlorobenzyl) phenoxy ] butane (EPK) At present, no document report of EP4 related substances and enantiomer inspection methods is found, related impurities of a conventional development scheme are separated by adopting an achiral chromatographic column and reversed-phase elution, enantiomers are separated by adopting a normal-phase system through the chiral chromatographic column, 2 analysis methods are required to be developed, and the defects of long commercial production inspection period and high cost are overcome. The research breaks through the conventional method development scheme, adopts a polysaccharide derivative bonding type filler chiral chromatographic column reversed phase gradient system for elution, solves the problem of chiral resolution of EP4 and EP4B, can rapidly elute dimer impurity EP4K, realizes the inspection method for simultaneously inspecting related impurities and EP4 enantiomer in EP4 by the same method parameters, has the advantages of high specificity, high sensiti