Preparation method of canagliflozin hemihydrate and monocrystal thereof

A technology of canagliflozin hemihydrate and single crystal, which is applied in organic chemistry and other fields, and can solve problems such as difficult quality control, inconvenient operation, and low yield

Inactive Publication Date: 2015-07-01
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] In this synthetic route, α-chloro-5-bromo-2-methylacetophenone is highly irritating, and odor will be produced during the thiophene ring closure reaction, which is inconvenient to operate; Methanesulfonic acid as a genotoxic impurity, and boron trifluoride ether as a dangerous reagent; moreover, this synthetic route will produce impurities that are difficult to remove, which brings difficulties to quality control
[0023] It is difficult to crystallize the preparation of canagliflozin hemihydrate in the above-mentioned prior art, and the intermediate steps are long, the intermediate steps are also difficult to crystallize, and the yield is low

Method used

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  • Preparation method of canagliflozin hemihydrate and monocrystal thereof
  • Preparation method of canagliflozin hemihydrate and monocrystal thereof
  • Preparation method of canagliflozin hemihydrate and monocrystal thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Synthesis of [5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-methylphenyl)methanone (II)

[0059]

[0060] The starting material 5-iodo-2-methylbenzoic acid (100.06g, 0.38mol) was added to 400ml of dichloromethane, stirred at room temperature, and N,N-dimethylformamide (1.89g, 0.026mol) was added dropwise , and then dropwise added oxalyl chloride (74.03 g, 0.58 mol), and stirred at room temperature for about 2 hours to complete the reaction. The reaction solution was evaporated under reduced pressure to remove the solvent to obtain a white solid for use.

[0061] Add aluminum trichloride (60.81g, 0.45mol) into 400ml of dichloromethane, stir at room temperature, then add 2-(4-fluorophenyl)thiophene (57.03g, 0.32mol), and then add the white solid obtained above, React at 20-25°C for 2 hours. After the reaction is complete, cool the reaction liquid to -10°C, then slowly add 200ml of water to quench, add 400ml of dichloromethane to extract twice, wash once with saturated sali...

Embodiment 2

[0075] Preparation of single crystal of canagliflozin hemihydrate (V)

[0076] Dissolve canagliflozin hemihydrate (1.52g) in methanol (10.00ml) at a temperature of 18°C ​​to 20°C, then add water (11.00ml) dropwise, mix well, use solvent evaporation method, crystal Grow to 18-20 days, can obtain the single crystal of canagliflozin hemihydrate of good quality, obtain single crystal data through X-ray diffraction as shown in Table 1, its single crystal structure model is as follows figure 1 shown.

[0077] Table 1: Single crystal data of canagliflozin hemihydrate

[0078]

[0079]

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Abstract

The invention relates to a preparation method of canagliflozin hemihydrate and monocrystal thereof, belonging to the technical field of canagliflozin hemihydrate. The method comprises the following steps: crystallizing the raw material 5-iodo-2-methyl benzoic acid by using canagliflozin hemihydrate monocrystal as a crystal seed to prepare the canagliflozin hemihydrate, and carrying out solvent volatilization in a methanol-water solvent environment to prepare the canagliflozin hemihydrate monocrystal. The preparation method of the canagliflozin hemihydrate is simple, has the advantages of high yield and low cost, and is suitable for industrial production. The preparation method of the canagliflozin hemihydrate monocrystal is simple and convenient, and can obtain the high-quality monocrystal compound.

Description

technical field [0001] The present invention relates to a preparation method of canagliflozin hemihydrate and its single crystal, in particular to using 5-iodo-2-methylbenzoic acid as raw material and using single crystal of canagliflozin hemihydrate as crystal seed The preparation of canagliflozin hemihydrate by crystallization, and the method of preparing canagliflozin hemihydrate single crystal by solvent volatilization method in the solvent environment of methanol and water belong to the technical field of canagliflozin hemihydrate. Background technique [0002] Canagliflozin (canagliflozin), the chemical name is (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]- 4-methylphenyl]-D-glucitol, its structural formula is as follows: [0003] [0004] Canagliflozin is the first sodium-glucose co-transporter 2 (SGLT2) inhibitor approved by the US FDA for the treatment of type 2 diabetes in adult patients. It can inhibit SGLT2 and prevent the smooth reabsorption...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10
CPCC07D409/10
Inventor 闫红王业明孙武积任绘君樊强文
Owner BEIJING UNIV OF TECH
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