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An intermediate and molar ratio technology, applied in the field of pharmaceutical chemical synthesis, can solve the problems of low yield, high equipment requirements, and high operational safety requirements
Active Publication Date: 2019-04-02
NEW FOUNDER HLDG DEV LLC +3
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Problems solved by technology
There are two steps in the synthesis route, which require a temperature of -70°C, which requires high equipment requirements; and the second step uses n-butyllithium, which requires high operational safety; the crystallization and purification step of crude canagliflozin has disadvantages such as low yield.
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Embodiment 1
[0091]The present embodiment is a kind of preparation method of canagliflozin, and described preparation method comprises the following steps:
[0092] 1. Preparation of Intermediate 1:
[0093] Take a 3L three-neck flask, install a mechanical stirrer, a thermometer and a constant pressure low liquid funnel; add 300ml of anhydrous tetrahydrofuran, add 100g (0.245mol) 2-(4-fluorophenyl)-5-[(5-iodo-2- Methylphenyl)methyl]thiophene, stir until dissolved; under nitrogen protection, cool down to -25~-20°C, add 263.8mL (0.343mol) sec-butylmagnesium chloride-lithium chloride / THF solution dropwise, add dropwise Complete, continue to react for 1 hour;
[0094] Maintain the temperature, add dropwise 171.6g (0.368mol) 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone pre-cooled to -25~-20°C Add to the reaction solution, wherein the 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone is dissolved in 200 mL of anhydrous tetrahydrofuran solution. After the dropwise addition, continue to re...
Embodiment 2
[0106] This embodiment is another preparation method of canagliflozin, the preparation method comprising the following steps:
[0107] 1. Preparation of intermediate 1:
[0108] Take a 2L three-necked flask, install a mechanical stirrer, a thermometer and a constant pressure low liquid funnel; add 150ml of anhydrous tetrahydrofuran, add 50g (0.122mol) 2-(4-fluorophenyl)-5-[(5-iodo-2- Methylphenyl)methyl]thiophene, stirred until dissolved; under nitrogen protection, and cooled to -25~-20°C, 122.5mL (0.159mol) of isopropylmagnesium chloride. Lithium chloride / THF solution was added dropwise, and the dropwise addition was completed After that, continue to react for 1 hour;
[0109] Maintain the temperature, drop 74.3g (0.159mol) of 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone pre-cooled to -25~-20°C Add to the reaction solution, wherein the 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone is dissolved in 100 mL of anhydrous tetrahydrofuran solution. After the dropwise add...
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Abstract
The invention relates to a preparation method of canagliflozin, and the preparation method is characterized in that the preparation method comprises the following steps: 1) reacting 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O-(trimethylsilyl)- D- glucolactone under a low-temperature condition, and carrying out methylation and deprotection reaction with a methanol solution of methanesulfonic acid to generate an intermediate 1; 2) under a low-temperature condition, reacting the intermediate 1 with triethyl silane and boron trifluoride diethyl etherate, and carrying out post-treatment to obtain an intermediate 2; 3) under a low-temperature condition, reacting the intermediate 2 with an organic base, DMAP and acetic anhydride,and purifying to obtain an intermediate 3; and 4) reacting the intermediate 3 with an alkaline water solution, and purifying after the reaction to obtain the canagliflozin. The method is mild in conditions, safe to operate, simple in post-treatment and high in product purity, no alpha-isomer is detected; the product is safer.
Description
technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to an industrialized preparation method of canagliflozin. Background technique [0002] Canagliflozin is the first drug approved among sodium-glucose co-transporter 2 (SGLT2) inhibitors for blood glucose in adults with type 2 diabetes. It acts on the SGLT2 protein in the kidney that helps reabsorb glucose, allowing more sugar to be excreted through the patient's urine, reducing blood sugar levels. The drug was jointly developed by Mitsubishi Tanabe of Japan and Johnson & Johnson of the United States, and was approved by the FDA in March 2013. The chemical name of canagliflozin: (1S)-1,5-dehydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylbenzene Base]-D-glucose hemihydrate, the molecular formula is C 24 h 25 FO 5 S.1 / 2H 2 O, the molecular weight is 453.5, the structural formula is as follows: [0003] [0004] At present, the preparation...
Claims
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Application Information
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