Canagliflozin new preparation method

A technology of canagliflozin and a synthesis method, applied in the field of pharmacy, can solve problems such as excessive reaction time, large amount of methanesulfonic acid, corrosion, etc., and achieves the advantages of reducing the amount of methanesulfonic acid, being extremely easy to recover and applying, and reducing costs. Effect

Inactive Publication Date: 2014-11-19
XIANGBEI WELMAN PHARMA CO LTD
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Problems solved by technology

Among them, route one (attached Figure 4), two ( Attached Figure 5) the method is similar but the synthesis sequence is different, among which The coupling conditions of 7 and 8 or 9 and 10 can be Grignard reagents and alkyl lithium reagents, but the Grignard reaction conditions are high, the initiation is difficult, and the conversion rate is low. In addition, the route 2 has a high solution viscosity at -78°C , the solubility of 5-bromo-2-chlorobenzoic acid is not good, and the conversion rate of aryllithium formed with n-butyllithium is not high and the polarity becomes larger. At the same time, carboxylic acid will also consume a large amount of expensive n-butyllithium Butyllithium, while the polarity of benzyl-protected gluconolactone is very small, so the reaction time is too long
In addition, n-butyl lithium and a small amount of lithium hydroxide will react with acid to produce water, which will affect the reaction yield.
The third point is that the raw material is excessive, the properties are not much different from the follow-up product and will participate in the follow-up reaction, the separation is difficult, and the product must be separated and purified by column chromatography, which also limits the industrial production of this route
[0014]First of all, the existing coupling operations all use 2-(4-fluorophenyl)-5-(5-iodo-2-methylphenyl)methylthiophene Or the reaction solution of 2-(4-fluorophenyl)-5-(5-iodo-2-methylphenyl)methylthiophene and n-butyllithium is kept at -78°C in 8 toluene at -78°C Dropping in the solution, the operation is difficult and requires high equipment
[0015]Secondly, the method of coupling and etherification in one pot is adopted, and the reaction process is not easy to monitor, especially the additional use of 1 equivalent of methanesulfonic acid to neutralize the Alkali, resulting in a particularly large amount of methanesulfonic acid, and methanesulfonic acid is not only expensive, but also highly acidic and has serious corrosive effects

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Embodiment 1

[0039] 1-[1-Hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[5-( Synthesis of 4-fluorophenyl)-2-thienylmethyl]benzene

[0040] Add compound 7 (84.00 g, 0.23 mol) into a 3000 mL dry three-neck flask, install a mechanical stirring paddle, install a tee on one side and connect it to the nitrogen bag, and install a constant pressure dropping funnel on the other side (sealed with a flip plug) ), fix the device. Nitrogen was exchanged three times, then 800 mL of toluene and 800 mL of THF were added, stirred to dissolve, cooled in liquid nitrogen-acetone, and at the same time, 90 mL of n-BuLi (0.24 mol, 2.7 M n-hexane alkane solution). After the temperature dropped below -78 °C, continue to stir for 20 min, then slowly add n-BuLi cyclohexane solution dropwise into the constant pressure dropping funnel, and the dropwise addition was completed within 30 min. Stirring was continued at this temperature for 30 min. Then the dropping funnel was replaced with a c...

Embodiment 2

[0043] 1-[1-Hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[5-( Synthesis of 4-fluorophenyl)-2-thienylmethyl]benzene

[0044] Add the compound 2-(4-fluorophenyl)-5-(5-iodo-2-methylphenyl)methylthiophene (70.40 g, 0.17 mol) into a 3000 mL dry three-necked flask, install a mechanical stirring paddle , One side is connected with a three-way connection with the nitrogen bag, and the other side is installed with a constant pressure dropping funnel (sealed by turning over the plug), and the device is fixed. Nitrogen was exchanged three times, then 700 mL of toluene and 700 mL of THF were added, stirred to dissolve, cooled in liquid nitrogen-acetone, and 114 mL of n-BuLi (0.18 mol, 1.6 M n-hexane solution). After the temperature dropped below -78 °C, continue to stir for 20 min, then slowly add n-BuLi cyclohexane solution dropwise into the constant pressure dropping funnel, and the dropwise addition was completed within 30 min. Stirring was continued at th...

Embodiment 3

[0047] Synthesis of 1-(1-methoxy-2-β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene

[0048] Dissolve the target product in Example 1 with 1000 ml of methanol, add 0.5 ml of methanesulfonic acid, react at 40°C for 2 h, distill off the solvent under reduced pressure, add 1000 ml of ethyl acetate, transfer to a separatory funnel, and successively saturated carbonic acid Wash with sodium hydrogen and saturated brine, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent on a rotary evaporator to obtain a raw brown solid, add 300 ml of toluene to mechanically stir to dissolve, add 1200 ml of cyclohexane, and precipitate an off-white solid product (90.48 g, 82.0% yield based on 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene).

[0049] ESI-MS m / z 460.2 (M+NH4-MeOH), 443.1 (M+H-MeOH). 1H NMR (400MHz, DMSO-d6): δ 2.26 (s, 3H), 2.92 (d, 1H, J= 8.4Hz), 2.96 (s, 3H), 3.22 (t, 1H, J=9.0Hz), 3.36-3.40 (m, 1H), 3.52-3.61 (m, 2H), 3.76 ...

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Abstract

The invention relates to a new synthetic method of 1-(beta-D-pyran glucosyl)-4-methyl-3-[5-(4-fluorinated phenyl)-2-thienyl methyl] benzene (canagliflozin), and the method is characterized in that: coupling and etherification steps are separately operated, at the same time in the etherification process, usage amount of methanesulfonic acid is greatly reduced compared with the prior art, and the method can reduce the cost, is convenient in operation and improves the quality of products.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a method for synthesizing medicaments, more specifically a method for synthesizing 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorobenzene) yl)-2-thienylmethyl]benzene (canagliflozin). [0002] Background technique [0003] With changes in lifestyle and economic conditions, global blood sugar levels and the incidence of diabetes are increasing year by year. Diabetes is mainly divided into type 1 diabetes with absolute insulin deficiency and type 2 diabetes with relative insulin deficiency (T2DM). About 90-95% of diabetic patients belong to T2DM. The prevalence of T2DM has increased significantly and is expected to reach 7.1% of the total adult population by 2025. Sustained high blood sugar can lead to many complications, such as retinal, renal, nervous system and microvascular complications, etc. Diabetes has become one of the most terrible killers threatening human life and health, and i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10
CPCC07D409/10
Inventor 王海勇肖鹏但飞君
Owner XIANGBEI WELMAN PHARMA CO LTD
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