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Preparation method of Dapagliflozin eutectic matter

A preparation process and co-crystal technology, which is applied in the direction of drug combinations, carbohydrate active ingredients, metabolic diseases, etc., can solve the problems of cumbersome treatment of pharmaceutical crystal solvent residues, cumbersome synthesis process and post-processing, and complicated reaction steps. Achieve the effect of convenient industrial production, low equipment requirements and easy operation

Inactive Publication Date: 2017-12-08
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] The technical problem solved by the present invention is to solve the complex reaction steps in the prior art related to the preparation of the dapagliflozin co-crystal, the synthesis process and post-treatment are relatively cumbersome, the reagents used are not easy to obtain, and the preparation of the pharmaceutical crystal form solvent residues Complicated problems, providing a preparation process for pharmaceutical dapagliflozin co-crystals that is more suitable for industrial production

Method used

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  • Preparation method of Dapagliflozin eutectic matter
  • Preparation method of Dapagliflozin eutectic matter
  • Preparation method of Dapagliflozin eutectic matter

Examples

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Embodiment 2

[0059] Example 2, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)

[0060] Add n-butyl ether (30mL) to zinc bromide (2.25g) and lithium bromide (0.87g), heat to 50°C and stir for 2h, cool for later use. Under nitrogen protection, add toluene (10mL) and n-butyl ether (10mL) to 4-(2-chloro-5-iodo-benzyl)phenetole (7.45g), cool to -20°C, and slowly add 1.6mol / L n-hexyllithium n-hexane solution (14mL), control the internal temperature not to exceed -10°C, after the dropwise addition, keep it at -20°C for 0.5h, add the spare n-butyl ether solution of zinc bromide and lithium bromide, and The reaction was stirred at 20°C for 3h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (11.59g) toluene (50mL) solution, heat to 120°C and stir for 4h. After the reaction is detected by TLC, Add 1mol / L dilute hydrochloric acid (40mL) and water (20mL) for extraction, wash the organic phase with water (40mL), wash wi...

Embodiment 3

[0061] Example 3, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)

[0062] Add n-butyl ether (40mL) to zinc bromide (3.38g) and lithium bromide (1.3g), heat to 50°C and stir for 2h, cool for later use. Under nitrogen protection, add toluene (20mL) and n-butyl ether (5mL) to 4-(2-chloro-5-iodo-benzyl)phenetole (7.45g), cool to -50°C, and slowly add 2.5mol / L n-butyllithium n-hexane solution (8mL), control the internal temperature not to exceed -30°C, after the dropwise addition, keep it at -50°C for 10 hours, add the above-mentioned spare n-butyl ether solution of zinc bromide and lithium bromide, The reaction was stirred at -20°C for 10 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (34.77g) toluene (80mL) solution, heat to 100°C and stir for 24h. After the reaction is detected by TLC, Add 1mol / L dilute hydrochloric acid (60mL) and water (50mL) for extraction, wash the organic phase with wate...

Embodiment 4

[0063] Example 4, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)

[0064] Add n-butyl ether (50mL) to zinc iodide (3.19g) and lithium iodide (1.34g), heat to 50°C and stir for 1.5h, then cool for later use. Under nitrogen protection, add toluene (15mL) and n-butyl ether (5mL) into 4-(2-chloro-5-iodo-benzyl)phenetole (7.45g), cool to -60°C, and slowly add 1.6mol / L n-hexyllithium n-hexane solution (13.8mL), control the internal temperature not to exceed -20°C, after the dropwise addition, keep it at -60°C for 5 hours, add the above-mentioned spare n-butyl ether solution of zinc iodide and lithium iodide , The reaction was stirred at 25 °C for 1 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (23.2g) toluene (50mL) solution, heat to 140°C and reflux for 0.5h, after the reaction is detected by TLC , add 1mol / L dilute hydrochloric acid (50mL), water (50mL), extract, the organic phase is washed wi...

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Abstract

The invention provides a preparation technology of a Dapagliflozin eutectic matter. The preparation technology comprises the following steps: (1) using 4-chlorin-3-(4-ethyoxyl benzyl) phenyl halide 6 as a raw material, carrying out an X / Li / Zn exchange reaction on the 6 with lithium alkylide and zinc salt in an appropriate solvent to prepare organic zinc reagent-di[4-chlorin-3-(4-ethyoxyl benzyl) phenyl] zinc, then carrying out a nucleophilic substitution reaction with 2,3,4,6-tetra-O-pivaloyl-alpha-D-bromo-glucopyranose 4 to prepare a compound 3; and (2) taking off a pivaloyl protecting group of a compound 3 to obtain Dapagliflozin 2, and directly reacting with (S)-1,2-propylene glycol and water in the appropriate solvent to prepare the Dapagliflozin eutectic matter 1. The synthetic route is as follows: the formula is as shown in the specification, wherein X in the 4-chlorin-3-(4-ethyoxyl benzyl) phenyl halide 6 structure is selected from bromine Br or iodine I. The reagent used in the route is a conventional reagent, and is low in cost and easily obtained; the route is simplified, the route cost is greatly reduced, the product yield and purity are relatively high, and a diastereoisomer is not contained in the product, so that the preparation technology is applicable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation process of a hypoglycemic drug dapagliflozin co-crystal. Background technique [0002] Dapagliflozin (English name: Dapagliflozin) is a new sodium-glucose co-transporter 2 (Sodium glucose co-transporters 2, referred to as SGLT-2) inhibitor developed by Bristol-Myers Squibb and AstraZeneca. It was approved for marketing by the European Commission on November 14, 2012, and was launched in the United States on January 8, 2014. It is used to combine diet and exercise to improve blood sugar control in adults with type 2 diabetes; the trade name is Farxiga, which currently provides 5mg and 10 mg tablet. At the same time, the compound preparation of Dapagliflozin and metformin hydrochloride has also been launched. [0003] The chemical name of Dapagliflozin is (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H -pyran-3,4,5-triol, the chemic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10
CPCC07B2200/13C07D309/10A61K31/70A61P3/10Y02P20/55
Inventor 马帅潘竞刘珍仁周伟澄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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