- Telescoped lithiation, C-arylation and methoxylation in flow-batch hybrid toward the synthesis of canagliflozin
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We report a highly efficient three-step flow-batch hybrid procedure for the synthesis of a key canagliflozin intermediate. The telescoped process provides exquisite control over an exothermic and mixing sensitive lithiation and subsequent C-arylation within a microstructured flow reactor. Methoxylation reagents are then added in flow, before reaching completion in a batch vessel. The flow process afforded the target intermediate in 76% yield, with a throughput of 26.8 g/h.
- Hone, Christopher A.,Oliver Kappe, C.,Polterauer, Dominik,Williams, Jason D.
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supporting information
(2021/09/22)
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- Preparation method and application of canagliflozin alpha isomer
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The invention discloses a preparation method and application of a canagliflozin alpha isomer, the preparation method comprises the following steps: in the presence of Lewis acid, a compound of formulaIV and a reducing agent are subjected to a reduction reaction in an organic solvent to obtain the canagliflozin alpha isomer, wherein the lewis acid is a mixture of trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate; the reducing agent is 1, 1, 3, 3-tetramethyldisiloxane. The preparation method is simple, the high-purity canagliflozin related substance reference substance can be rapidly obtained, the yield of the product canagliflozin alpha isomer is 37.5%, the purity is as high as 97.61%, the purity requirement of a standard substance is completely met, and the canagliflozin alpha isomer can be used as the standard substance and can be applied to quality control and research of canagliflozin bulk drugs. Therefore, the quality control level of canagliflozin is improved, andthe clinical medicinal safety is ensured.
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Paragraph 0019; 0027-0030
(2021/01/25)
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- Method for preparing intermediates of gliflozin hypoglycemic drugs
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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.
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Paragraph 0043; 0046-0047; 0050
(2020/05/02)
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- Preparation method of high-purity canagliflozin intermediate
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The invention discloses a preparation method of a high-purity canagliflozin intermediate, which comprises the following steps: reacting a thiophene compound with an alkaline reagent in an inert environment at low temperature, and condensing the reaction product with 2, 3, 4, 6-tetra-O-(trimethylsilyl)-D-glucolactone; dropwise adding a strong acid aqueous solution into the obtained reaction solution, quenching after reaction, separating out an organic phase for concentrating, and performing crystallizing and drying to obtain an intermediate I; reacting the intermediate I with strong acid in methanol to obtain a high-purity canagliflozin intermediate II. By preparing the intermediate I with excellent crystallization performance, the purity of the canagliflozin intermediate II is improved. The operation is simple and convenient, the production process is stable, and industrial production is facilitated.
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Paragraph 0045; 0047-0060; 0062-0073; 0076-0078; 0081
(2020/08/30)
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- Preparation method of Canagliflozin intermediate
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The invention provides a preparation method of a Canagliflozin intermediate. According to the method, a stable reagent is added to an organic solvent mixing system containing 2-(5-BroMo-2-Methylbenzyl)-5-(4-fluorophenyl)thiophene(compound III) and n-Butyllithium, so that the phenomenon that when the n-Butyllithium is used, reaction products are complex, and more by-products exist, can be improved.The method is stable and high in repetition rate, the purity of the obtained intermediate is as high as 94.7%, the continuous reaction yield can achieve 93.8%, and the preparation method has industrial application prospects.
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Paragraph 0115-0122; 0143-0144
(2019/11/13)
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- Preparation method of canagliflozin
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The invention relates to a synthesis method of canagliflozin. According to the synthesis method, 4-fluorophenylboronic acid is taken as an initial raw material to be coupled with 5-bromo-thiophene-2-formaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-formaldehyde, the 5-(4-fluorophenyl)thiophene-2-formaldehyde undergoes reduction and chlorination and then undergoes Friedel-Crafts alkylation reaction with 4-bromotoluene to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and the 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene undergoes condensation, etherificationand methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The preparation method has the following advantages: compared with the conventional preparation methods, the synthesis process takes the 4-fluorobenzeneboronic acid as an initial raw material, so that the raw material is cheap and easy to get, the process is easy to realize industrialization, the synthesis route is short and the operation is easy; in the synthesis process, bromine is not used or butyl lithium does not need to be used twice, so that the risk of the process can be reduced; in addition, the preparation method is capable of improving the yield of canagliflozin products to 70% or more.
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- PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF CANAGLIFLOZIN
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The present invention relates to an improved process for the preparation of amorphous form of Canagliflozin with high purity and high yield. Particularly the present invention is related to the direct isolation of amorphous form of Canagliflozin from reaction mixture and also related to purification of amorphous form of Canagliflozin through piperidine-4-carboxylic acid complex of Canagliflozin.
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Page/Page column 12; 13
(2018/02/28)
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- Synthesis and Optimization of Canagliflozin by Employing Quality by Design (QbD) Principles
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Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel-Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.
- Metil, Dattatray S.,Sonawane, Swapnil P.,Pachore, Sharad S.,Mohammad, Aaseef,Dahanukar, Vilas H.,McCormack, Peter J.,Reddy, Ch. Venkatramana,Bandichhor, Rakeshwar
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- Method for continuously preparing canagliflozin by using microreactor one-pot method
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The invention discloses a method for continuously preparing canagliflozin by using a microreactor one-pot method. The method is used for continuously preparing the canagliflozin by using the microreactor one-pot method, and microreactors are divided into a unit A, a unit B, a unit C and a unit D. The method comprises the steps of mixing a solution of M1 with n-butyl lithium in the unit A for carrying out a reaction; after the reaction is finished, enabling the reaction product to enter the unit B together with a solution of M3, and carrying out a reaction at the temperature of -15 to -5 DEG C to obtain an intermediate A; enabling reaction liquid containing the intermediate A to enter the unit C together with a methanol solution of methane sulfonic acid, and carrying out a reaction to obtain an intermediate B; enabling reaction liquid containing the intermediate B to directly react with boron trifluoride and triethyl silicane in the unit D to obtain the canagliflozin. The method greatly simplifies the operation steps, shortens the reaction time, greatly reduces the use of various solvents, lowers the production cost, improves the production safety, can realize continuous and automatic production, and is high in product purity and yield, thus being suitable for industrial production.
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Paragraph 0025; 0052; 0054
(2017/07/19)
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- PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL AGENT
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This invention provides a process for preparing canagliflozin, comprising: (a) reacting a tricyclic aromatic derivative and a substituted cyclic ester, quenching and deprotecting the resulting intermediate to provide a compound comprising a substituted tetrahydropyran-tricyciic aromatic derivative, and (b) reducing the tetrahydropyran-tricyclic aromatic derivative to provide canagliflozin. The invention also provides a process for preparing canagliflozin hemihydrate.
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Page/Page column 11
(2017/05/17)
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- Canagliflozin intermediate preparation method
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The invention provides a canagliflozin intermediate preparation method. The method comprises the following steps: adding 2,3,4,6-tetra-O-(trimethyl silicon)-D-gluconic acid-delta-lactone and 2-(4-fluorophenyl)-5-[(5-iodine-2-methyl phenyl)methyl]thiophene in an organic solvent A, adding an alkalescence reagent under low temperature condition, completely reacting the materials and then adding an acidic alcoholic solution for deprotection and acid treatment, adding an alkaline solution for adjusting a pH value to 7-8, standing for separating an organic layer, extracting a water layer by using an organic solvent B, merging the organic layer, washing the material, drying the material, filtering the material, and concentrating the material to obtain an oily substance, crystallizing the oily substance, and filtering the product to obtain a canagliflozin intermediate. The preparation method has the advantages of simple reaction operation and is suitable for industrial production, yield is high and purity is good.
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Paragraph 0032; 0033; 0034; 0035; 0036
(2016/11/21)
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- Preparation method of SGLT-2 inhibitor compound
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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.
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- C-ARYL GLUCOSIDE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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C-aryl glucoside derivatives, preparation processes and pharmaceutical uses thereof are disclosed. In particular, C-aryl glucoside derivatives represented by formula (I), with each substituent defined in the application, pharmaceutically acceptable salts or stereoisomers thereof, their preparation methods, and pharmaceutical compositions containing the derivatives as well as their uses as therapeutic agents, particularly as sodium-dependent glucose cotransporter (SGLT)-1 inhibitors, are disclosed.
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