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4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs

A kind of fluorobenzyl, C1-C3 technology, applied in 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene and its preparation and application field in the preparation of anti-type II diabetes drugs as an intermediate , which can solve the problems of limited synthesis routes, and achieve the effects of good yield, simple and safe operation, and good economic effect.

Inactive Publication Date: 2014-09-17
SHANGHAI FANGNAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, the synthetic pathways for this compound are relatively limited

Method used

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  • 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs
  • 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs
  • 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs

Examples

Experimental program
Comparison scheme
Effect test

example 14

[0029] The synthesis of example 14-bromo-1-chloro-2-(4-fluorobenzyl)benzene (Va)

[0030] Add (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone (VIa, 31.3g, 100mmol) and 190mL of dichloromethane into a 500mL three-necked flask, stir and dissolve at room temperature, then cool down to 0-5°C , slowly drop triethylsilane (44.2g, 380mmol), then slowly add boron trifluoride diethyl ether (51.8g, 365mmol) dropwise at a controlled temperature between 0 and 5°C, and return to 20-30°C for 4-6 Hours, HPLC traced to raw material remainder<3%. Add 150 mL of saturated aqueous sodium bicarbonate solution to the reaction flask, stir for 30 minutes, and separate the liquids. The organic phase was concentrated until no distillate flowed out, 230 g of deionized water was added, stirred until solid precipitated, and filtered. Dissolve the solid in 110mL of acetonitrile, add dropwise 110mL of 2% sodium hydroxide aqueous solution, stir, filter the system, wash the filter cake with a little water...

example 2

[0032]Synthesis of Example 21-chloro-2-(4-fluorobenzyl)-4-iodobenzene (Vb)

[0033] Add (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone (VIb, 36.1g, 100mmol) and 180mL acetonitrile into a 500mL three-necked flask, stir and dissolve at room temperature, then cool down to 0-5°C, slowly Add triethylsilane (44.2g, 380mmol) dropwise, then slowly add boron trifluoride diethyl ether (51.8g, 365mmol) dropwise at a controlled temperature of 0-5°C, return to 20-30°C and react for 4-6 hours, HPLC Track until the remaining raw material is less than 3%. Add 150 mL of saturated aqueous sodium bicarbonate solution to the reaction flask, stir for 30 minutes, and separate the layers. Concentrate the organic phase to 95-110 mL, add 230 g of deionized water, stir until solid precipitates, and filter. The solid was rinsed with acetonitrile / water=1 / 3 system (100mL), and dried to obtain an off-white solid, namely the compound 1-chloro-2-(4-fluorobenzyl)-4-iodobenzene (Vb) (27.4 g, yield 79%). ...

example 3

[0035] Example 3 (2S, 3R, 4S, 5R, 6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-(4-fluorobenzyl Synthesis of (yl)phenyl)-2-methoxytetrahydro-2H-pyran (IVa)

[0036] Method 1): Add 4-bromo-1-chloro-2-(4-fluorobenzyl)benzene (Va, 3g, 10mmol) and 15mL THF into a three-necked flask, cool down to -78°C under nitrogen protection, and slowly add positive Butyl lithium in n-heptane (10 mL, 10 mmol) was added dropwise, and stirred at -78°C for 1 hour. Add (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one dropwise at -78°C THF solution (VIIa, 5.4g, 10mmol, dissolved in 6mL THF), the system was reacted at -78°C for 1 hour. After that, 20 mL of methanol solution containing 1.5 mL of methanesulfonic acid was added, and the system was warmed to room temperature and stirred overnight. Add saturated aqueous sodium bicarbonate solution to the system to quench the reaction, separate the layers, extract the aqueous phase twice with 50 mL of ethyl a...

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Abstract

The invention discloses a compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene shown as formula V, its preparation method and application as an intermediate in preparation of anti-type II diabetes drugs, and especially discloses the compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene shown as formula V and its application as an intermediate in preparation of anti-type II diabetes drug Empagliflozin shown as formula I. The method provided by the invention has the advantages of relatively cheap raw material and reagent, low cost, simple and safe operation, good yield, small environmental pollution, and very good economic effect, thus being suitable for industrial production.

Description

technical field [0001] The present invention relates to a compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene as shown in formula V and its preparation method and its application as an intermediate in the preparation of anti-type II diabetes drugs, especially It relates to a compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene as shown in formula V and its use as an intermediate for preparing the anti-type II diabetes drug Empagliflozin as described in formula I. technical background [0002] Empagliflozin (formula I below, CAS: 864070-44-0) is being developed by Boehringer Ingelheim in a new generation of compounds known as sodium-glucose cotransporter-2 (SGLT-2) inhibitors One, it can provide the effect of reducing high blood glucose level (hyperglycemia) independent of insulin, and its mechanism of action is to block the reabsorption of glucose in the kidney, thereby excreting excess glucose in the body through urine to lower blood sugar At the same time and f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C25/18C07C17/35C07H7/04C07H1/00
CPCY02P20/55
Inventor 丹尼尔·张
Owner SHANGHAI FANGNAN PHARMA
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