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

A technology of thienylmethyl and glucopyranosyl, which is applied in the field of synthesis technology of 1--4-methyl-3-[5--2-thienylmethyl]benzene, can solve the problems of high cost and route long, low total yield, etc., to achieve the effects of controlling production costs, cheap and easy-to-obtain raw materials, and mild conditions

Active Publication Date: 2017-10-31
JIANGSU SINOBIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Disadvantages: Low temperature (<-70°C) is required, anhydrous and oxygen-free, and the lithium reagent formed by iodide is relatively unstable
[0010] Disadvantages: The route is long, and the two intermediates are oily, which is not conducive to purification and separation
[0014] Disadvantages: low temperature (<-40°C) is required, anhydrous and oxygen-free environment is required, pivaloyl chloride is smelly, zinc bromide and TMSBr are sensitive to moisture, and the three-dimensional configuration is not easy to control
[0015] The existing synthetic routes reported in the literature have harsh process conditions. If column purification is required, the requirements for production equipment are high; if low temperature environment is required, the cost of industrialization is high; The yield is low, the environment is polluted, and it is not conducive to industrial production

Method used

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  • Synthesis of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
  • Synthesis of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
  • Synthesis of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Within 1 hour, in the temperature range of 0 ~ 10 ℃, the Turbogrignard solution (isopropylmagnesium chloride / lithium chloride solution, 14% by weight i-PrMgCl and LiCl in THF, molar ratio LiCl:i-PrMgCl=0.9 To 1.1mol / L) (5.4kg) was added to the tetrahydrofuran (10.0kg) solution of iodide (2.0kg). When the addition was complete, conversion was determined via HPLC analysis.

[0033] The reaction was considered complete when the peak area of ​​the corresponding iodide was less than 5.0% of the total area of ​​the two peaks (iodide and the corresponding deiodinated compound of iodide). If the reaction is not complete, add Turbogrignard solution until the standard is met. In this particular case, the result is 0.51%.

[0034] Then 2,3,4,6-O-tetrapivaloyl-α-D-bromoglucopyranose (2.9 kg) was added within 1 hour at 0-10°C. The resulting mixture was further stirred at 0-10°C for 2 hours. When the addition was complete, conversion was determined via HPLC analysis.

[0035] Re...

Embodiment 2

[0043] Within 1 hour, in the temperature range of 0 ~ 10 ℃, the Turbogrignard solution (isopropylmagnesium chloride / lithium chloride solution, 16% by weight s-BuMgCl and LiCl in THF, molar ratio LiCl:i-PrMgCl=0.9 To 1.1mol / L) (5.6kg) was added to the tetrahydrofuran (10.0kg) solution of iodide (2.0kg). When the addition was complete, conversion was determined via HPLC analysis.

[0044] The reaction was considered complete when the peak area of ​​the corresponding iodide was less than 5.0% of the total area of ​​the two peaks (iodide and the corresponding deiodinated compound of iodide). If the reaction is not complete, add Turbogrignard solution until the standard is met. In this particular case, the result is 0.51%.

[0045] Then 2,3,4,6-O-tetrapivaloyl-α-D-bromoglucopyranose (2.9 kg) was added within 1 hour at 0-10°C. The resulting mixture was further stirred at 0-10°C for 2 hours. When the addition was complete, conversion was determined via HPLC analysis.

[0046]Rea...

Embodiment 3

[0054] Within 1 hour, in the temperature range of 0 ~ 10 ℃, the Turbogrignard solution (isopropylmagnesium chloride / lithium chloride solution, 14% by weight i-PrMgCl and LiCl in THF, molar ratio LiCl:i-PrMgCl=0.9 To 1.1mol / L) (5.4kg) was added to the tetrahydrofuran (10.0kg) solution of iodide (2.0kg). When the addition was complete, conversion was determined via HPLC analysis.

[0055] The reaction was considered complete when the peak area of ​​the corresponding iodide was less than 5.0% of the total area of ​​the two peaks (iodide and the corresponding deiodinated compound of iodide). If the reaction is not complete, add Turbogrignard solution until the standard is met. In this particular case, the result was 0.63%.

[0056] Then 2,3,4,6-O-tetrapivaloyl-α-D-bromoglucopyranose (2.9 kg) was added within 1 hour at 0-10°C. The resulting mixture was further stirred at 0-10°C for 2 hours. When the addition was complete, conversion was determined via HPLC analysis.

[0057] R...

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Abstract

The invention discloses a preparation method of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene. The method has the advantages of short route, no need for low temperature, solid starting materials and intermediates, convenient purification and good stereoselectivity.

Description

technical field [0001] The invention relates to a synthesis process of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene. Background technique [0002] Canagliflozin belongs to the SGLT-2 inhibitor, which can specifically inhibit the reabsorption of glucose by the kidney. More importantly, the SGLT-2 inhibitor does not depend on the action of insulin, does not depend on the dysfunction of β cells or insulin resistance To a certain extent, its effect will not decline with the failure of β-cell function or severe insulin resistance, it will not produce adverse reactions caused by traditional drugs, and it can delay the development of the disease. It is a new way for the treatment of diabetes. [0003] Janssen Pharmaceutical NV reported the route of TMS protecting group in patent WO2005012326. The synthetic route is as follows: [0004] [0005] Advantages: There are multiple purifiable intermediates; [0006] Disadvantages: Low temperature (&l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/10
CPCY02P20/55
Inventor 黄乐群王磊邓海存
Owner JIANGSU SINOBIOPHARMA
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