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Preparation method of strontium ranelate key intermediate 3-ketoglutaric acid diethyl (dimethyl) ester

A technology of diethyl oxoglutarate and strontium ranelate, which is applied in the field of drug synthesis, can solve problems such as long production cycle, difficult handling, and high corrosion of equipment, so as to improve the reaction speed, shorten the reaction time, and reduce the cost of raw materials. low effect

Inactive Publication Date: 2014-07-09
NINGBO LIWAH PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When concentrated sulfuric acid is often used as a catalyst for esterification reaction, it is a low-cost homogeneous catalyst with good catalytic effect, but at the same time of esterification reaction, concentrated sulfuric acid has oxidation effect, which will cause a series of side reactions to occur, and give the product post-treatment Difficulty arriving
Although this method has a simple reaction and a high yield, the finished product is easy to decompose, and the product purity is not high. The process is complicated, the catalyst is difficult to recycle, and the amount of acidic wastewater in post-treatment and washing is large, which pollutes the environment and does not meet the current environmental protection requirements. Especially, chlorosulfonic acid is a highly toxic substance, which limits its industrial application.

Method used

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  • Preparation method of strontium ranelate key intermediate 3-ketoglutaric acid diethyl (dimethyl) ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1: SO 4 2- / TiO 2 Type or S 2 o 8 2- / TiO 2 Preparation of solid super acid

[0018] Dissolve 3000 mL tetrabutyl titanate in 3000 mL absolute ethanol, add glacial acetic acid dropwise under stirring at room temperature, continue stirring after the addition, and then add 4500 mL concentration of 0.6 mol L -1 of (NH 4 ) 2 SO 4 or (NH 4 ) 2 S 2 o 8 solution, continue to stir, put the mixed solution in a water bath at 80 °C for sol-gel conversion, after the gel is aged, put it in a drying oven at 70 °C for 24 h to obtain a dry gel, crush it and place it at 600 °C Calcined for 3 h to obtain the desired solid acid catalyst sample.

Embodiment 2

[0019] Example 2: SO 4 2- / SnO 2 , SO 4 2- / ZrO 2 , SO 4 2- / ZnO,SO 4 2- / Fe 2 o 3 , S 2 o 8 2- / SnO 2 , S 2 o 8 2- / ZrO 2 , S 2 o 8 2- / ZnO, and S 2 o 8 2- / Fe 2 o 3 Preparation of Type Solid Superacid

[0020] at 10% Fe 2 (SO 4 ) 3 / SnCl 2 / ZnSO 4 / Zr(SO 4 ) 2 Add concentrated ammonia water to the aqueous solution, adjust the pH to 9-10, obtain a precipitate, wash it with water until it is neutral, dry it at 120°C, and then grind it to obtain a powder, pass it through a 100-mesh sieve, and use a concentration of 1 mol L -1 of (NH 4 ) 2 SO 4 or (NH 4 ) 2 S 2 o 8 The solution was soaked for 2 hours, dried at 120°C for 12 hours after centrifugation, and roasted at 600°C for 3 hours to obtain the desired SO 4 2- / SnO 2 , SO 4 2- / ZrO 2 , SO 4 2- / ZnO,SO 4 2- / Fe 2 o 3 , S 2 o 8 2- / SnO 2 , S 2 o 8 2- / ZrO 2 , S 2 o 8 2- / ZnO, and S 2 o 8 2- / Fe 2 o 3 type solid superacid catalyst samples.

Embodiment 3

[0021] Embodiment 3: the preparation of 3-oxoglutaric acid diethyl ester

[0022] Add 1400g of ethanol to a 10L three-neck flask, cool down to -5°C, and put in SO 4 2- / TiO 2 or S 2 o 8 2- / TiO 2 Add 140g of solid superacid catalyst, then add 700g of citric acid monohydrate and slowly raise the temperature. There are bubbles (carbon monoxide) during the heating process. Heat to 25°C for 1 hour of time-preservation reaction. After no obvious bubbles, heat to 50°C for 3 hours of time-preservation reaction, and filter The filtrate and filter cake are recovered from the solid super acid catalyst and applied mechanically. After the ethanol is recovered from the filtrate, the reaction solution is slowly poured into ice water (below 10°C), and 2000ml of dichloromethane is added to stir and stand for stratification. Take the organic phase, and the organic phase is bright yellow. , The water phase is slightly white and turbid, the water phase is extracted with 500mL×2 times of di...

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Abstract

The invention discloses a preparation method of strontium ranelate key intermediate 3-ketoglutaric acid diethyl (dimethyl) ester. The method comprises the steps of firstly adding a solvent into a reactor, cooling, putting a solid super acidic catalyst, then putting citric acid monohydrate, slowly heating, performing a thermal reaction, heating until the thermal reaction ends after no obvious bubbles exist, filtering to obtain filtrate, recycling a filter cake as a catalyst, performing solvent recovery on the filtrate, adding into ice water, extracting by adding dichloromethane, washing an extract by using a sodium bicarbonate aqueous solution, water and a saturated saline solution in sequence, and performing reduced pressure distillation to obtain a product, wherein the catalyst is solid super-acid; reaction conditions are as follows: the reaction temperature is between -20 DEG C and 60 DEG C, and the reaction time is 2-12 hours (the sum of the heat preservation time). The process disclosed by the invention does not use any liquid acid catalyst, is mild in reaction, short in steps and simple and convenient in operation, can not cause acid wastewater discharge, and is green and environment-friendly.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of strontium ranelate key intermediate 3-oxoglutaric acid diethyl (methyl) ester. Background technique [0002] Osteoporosis is a systemic and systemic skeletal disease characterized by decreased bone mass and microarchitectural destruction of bone tissue leading to increased bone fragility and increased risk of fracture. The disease usually affects bones throughout the body, with fractures being the main complication of osteoporosis, most commonly causing fractures of the spine and hips. There are more than 200 million people over the age of 60 in my country, and we have entered an aging society. Among them, 1 / 3 of the elderly aged 60 to 70 suffer from osteoporosis, and women over the age of 80 suffer from the disease more, accounting for 2 / 3. The incidence of osteoporosis is gradually increasing, and it is necessary to use safe and ...

Claims

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Application Information

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IPC IPC(8): C07C69/716C07C67/32C07C67/08B01J27/053B01J27/02
CPCC07C67/32B01J27/02B01J27/053C07C51/38C07C67/08
Inventor 陈胜胜王学政林爱弟
Owner NINGBO LIWAH PHARM CO LTD
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