- IMPROVED PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN AND ITS CRYSTALLINE POLYMORPH
-
The present invention relates to an improved method for the production of Empagliflozin formula (I). The invention further relates to the preparation of a crystalline form of Empagliflozin and its particle size having a coarser particle or a D50 equal to or greater than 60 μm and a D90 equal to or greater than 180 μm. (I)
- -
-
Page/Page column 4; 9-11
(2021/12/31)
-
- Method for preparing intermediates of gliflozin hypoglycemic drugs
-
The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing key intermediates of gliflozin hypoglycemic drugs, in particular to a preparation methodof key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin. The method comprises the following steps: 1) in the presence of a cosolvent, carrying out halogen metal exchange on a raw material, namely aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and carrying out a nucleophilic addition reaction on the aryl lithium reagent 3 and TMS-protected glucolactone 4 to obtain a transition product 5; and 2) removing a TMS protecting group from the transition product 5, and converting hemiketal into ketal to obtain the key intermediate 1with a single configuration. According to the method, the key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin can be stereoselectively synthesized, reaction yield isrelatively high (more than 75%), and product purity is high (wherein HPLC purity is about 95%); so reduction preparation of a final product in the next step is facilitated.
- -
-
Paragraph 0055; 0058
(2020/05/02)
-
- Preparation and refining method of high-purity enzagliflozin (by machine translation)
-
Firstly, under the condition of ensuring the yield of the crude product, the purity of, the crude product is improved to the purity of the, crude product, so, that the refining and purifying times; are obviously reduced and further, optimized and refined. (by machine translation)
- -
-
Paragraph 0068-0071
(2020/01/25)
-
- Preparation method suitable for industrial production of empagliflozin
-
The invention belongs to the technical field of organic synthesis route design and medicine and chemical engineering, particularly relates to a synthesis method of a sodium-glucose cotransporter 2(SGLT2) inhibitor, and more particularly relates to a preparation method of empagliflozin. The empagliflozin is synthesized by taking (3S)-3-[4-[(2-chloro-5-iodophenyl) methyl] phenoxy] tetrahydrofuran and glucono delta-lactone as initial raw materials through a series of substep reactions such as protection, addition, substitution, deprotection and reduction. In the synthesis steps disclosed by the invention, a staged target product does not need to be separated and purified after each step of reaction, and the target product is finally obtained by directly subjecting a high-purity reaction intermediate to subsequent steps. The preparation method is simple in process, simple and convenient to operate and good in industrial prospect.
- -
-
-
- Refining method of SGLT-2 inhibitor intermediate
-
The invention discloses a refining method of an SGLT-2 inhibitor intermediate; the SGLT-2 inhibitor intermediate is represented by the formula (I), wherein the definition of substituent groups in theformula (I) is detailed in the specification. The refining method includes the following steps: the SGLT-2 inhibitor intermediate is dissolved in a polar organic solvent and cooled to ultra-low temperature, the non-polar organic solvent is added, and the solid SGLT-2 inhibitor intermediate is obtained. The refining method is different from a conventional recrystallization technology, and can refine materials that are not easy to solidify at room temperature. A new choice is provided for refining the materials with low melting point and high viscosity. The refining method is suitable for industrialized scale-up production.
- -
-
-
- Preparation method of empagliflozin
-
The invention relates to a preparation method of empagliflozin. The preparation method of empagliflozin comprises the following steps: taking 2-chlorobenzaldehyde as a starting material; carrying outbromination reaction, reduction reaction and halogenating reaction on the starting material, and carrying out Friedel-Crafts alkylation reaction on the starting material and (S)-3-phenoxyl tetrahydrofuran to obtain an intermediate which is (S)-3-(4-(5-bromo-2-chlorobenzyl) phenoxyl) tetrahydrofuran; and then carrying out condensation, etherification and methoxyl removal on the intermediate and 2,3,4,6-quadri-O-trimethylsilyl-D-glucolactone to obtain the empagliflozin as a hypoglycemic drug. The preparation method of the empagliflozin has the advantages that compared with an existing synthesisprocess, the preparation method of the empagliflozin takes the 2-chlorobenzaldehyde as the starting material, raw materials are cheap and easy to obtain, industrialization is easy to implement in theprocess, the synthesis route is short, and the method is easy to operate; in a preparation process, various temperature conditions are easy to control, reaction conversion rate is high, and the totalyield can be 75% or above; and moreover, by the preparation method, the product cannot be isomerized easily, impurities are fewer, the purity of the product can be improved, and the purity can be 99%or above.
- -
-
-
- Preparation method of SGLT2 inhibitor-empagliflozin
-
The invention relates to a preparation method of a SGLT2 inhibitor-empagliflozin. The preparation method includes: using 2-methylaniline as a starting raw material, subjecting the starting raw material to bromination, diazotization, chlorination and bromination, and enabling the starting raw material to be in friedel-crafts alkylation reaction with (S)-3-phenoxy tetrahydrofuran to obtain an intermediate-(S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran; subjecting the intermediate and 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone to condensation, etherification and methoxy removal.The preparation method has the advantages that compared with existing synthetic methods, 2-methylaniline is used as the starting raw material, so that the raw material is low in cost and easy to get,the process is easy for industrialization, and a synthetic route is short and easy to operate; in the process of preparation, temperature conditions are easy to control, reaction conversion rate is high, and total yield is up to higher than 75%. In addition, through the preparation method, the inhibitor is less prone to isomerization, impurities are few, and purity of the inhibitor can be improvedto higher than 99%.
- -
-
-
- Synthesis process for empagliflozin
-
The invention relates to a synthesis process for empagliflozin. The synthesis process for empagliflozin comprises the following steps: taking 4-fluorotoluene as a starting material; carrying out radical bromo reaction, Friedel-Crafts alkylation reaction, deprotection, diazotization chlorination and alkylation reaction to obtain an intermediate which is (S)-3-(4-(5-bromo-2-chlorobenzyl) phenoxyl) tetrahydrofuran; and then carrying out condensation, etherification and methoxyl removal on the intermediate and 2,3,4,6-quadri-O-trimethylsilyl-D-glucolactone to obtain the empagliflozin as a hypoglycemic drug. The synthesis process for empagliflozin has the advantages that compared with an existing synthesis process, the synthesis process for the empagliflozin takes the 4-fluorotoluene as the starting material, raw materials are cheap and easy to obtain, industrialization is easy to implement in the process, the synthesis route is short, and the process is easy to operate; in a preparation process, various temperature conditions are easy to control, reaction conversion rate is high, and the total yield can be 70% or above; and moreover, by the synthesis process, the product cannot be isomerized easily, impurities are fewer, the purity of the product can be improved, and the purity can be 99% or above.
- -
-
-
- Method for preparing high purity Empagliflozin
-
The present invention provides an improved method for preparing high purity Empagliflozin, the method includes the following steps: step a. under the protection of nitrogen, performing reaction of compounds 1 and 2 to obtain a compound 3; step b. adding the compound 3 into a reactor, adding methanol, dropwise adding concentrated hydrochloric acid, stirring, dissolving, clarifying, and performing reaction at room temperatur to obtain a compound 4; step c. adding dropwise an acetonitrile and dichloromethane solution of the compound 4 to an aluminium chloride, triethyl silicane, acetonitrile and dichloromethane solution for reaction, after completion of the reaction, adding water for quenching the reaction, stirring until a solid is precipitated, filtering by suction, and collecting a filter cake to obtain a crude product of compound 5, namely Empagliflozin; and d. refining the crude product. The method is suitable for industrial production,and can be used for the preparation of the high purity Empagliflozin.
- -
-
Paragraph 0033; 0034
(2017/10/13)
-
- Method for preparing empagliflozin
-
The invention provides a method for preparing empagliflozin. The method comprises the following steps: by taking (S)-3-(4-(5-bromine-2-chlorobenzyl) phenoxyl) tetrahydrofuran and glucolactone as initial raw materials, performing coupling so as to obtain an intermediate compound 3, performing etherification so as to obtain an intermediate compound 4, performing reduction so as to obtain a crude empagliflozin compound 5, and performing refining, thereby obtaining a qualified empagliflozin finished product.
- -
-
Paragraph 0071; 0072; 0073; 0074; 0075
(2017/08/29)
-
- Preparation method of SGLT-2 inhibitor compound
-
The invention relates to a preparation method of SGLT-2 inhibitor compound. The preparation method comprises the following steps: performing hydroxyl protection, coupling reaction, hydroxyl de-protection, ketalation and the like to the compound A so as to obtain an intermediate I; and then preparing the SGLT-2 inhibitor compound by the obtained intermediate I.
- -
-
Paragraph 0034; 0035
(2016/10/09)
-
- Efficient synthesis of empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3-promoted silane reduction of a β-glycopyranoside
-
An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin (5) from acid 1 is described. The key tactical stage involves I/Mg exchange of aryl iodide 2 followed by addition to glucono lactone 3 in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside 4 which is, without isolation, directly reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH 2Cl2/MeCN to afford 5 in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch.
- Wang, Xiao-Jun,Zhang, Li,Byrne, Denis,Nummy, Larry,Weber, Dirk,Krishnamurthy, Dhileep,Yee, Nathan,Senanayake, Chris H.
-
p. 4090 - 4093
(2014/10/15)
-
- METHOD FOR THE PREPARATION OF A CRYSTALLINE FORM OF 1-CHLORO-4- (BETA-D-GLUCOPYRANOS-1-YL)-2-(4-((S)-TETRAHYDROFURAN-3-YLOXY)BENZYL)BENZENE
-
The invention relates to a method for the preparation for a crystalline form of 1-chloro-4-(Β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene. In addition the invention relates to a crystalline form obtainable by this method, to a pharmaceutical composition and to the use thereof for preparing medicaments.
- -
-
Page/Page column 21-23
(2011/04/25)
-