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A kind of method for preparing loxoprofen active metabolite

A technology of compound and chiral auxiliary agent, which is applied in the field of synthesis of trans-hydroxyl active metabolites, can solve the problems that are not suitable for large-scale production energy consumption, difficult to obtain reagents, harsh conditions and other problems, so as to achieve simple operation and avoid purification Steps, high safety effect

Active Publication Date: 2018-03-27
NANJING HERON PHARMA SCI & TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] This document forms the skeleton structure of loxoprofen hydroxyl by preparing active organic copper intermediates, but the conditions are harsh, the yield is low, the reagents are not easy to obtain, and the reaction time is as long as 92h in the process of primary alcohol oxidation into carboxyl , not suitable for mass production requirements for energy consumption

Method used

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  • A kind of method for preparing loxoprofen active metabolite
  • A kind of method for preparing loxoprofen active metabolite
  • A kind of method for preparing loxoprofen active metabolite

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Synthesis of embodiment 1 formula 2 compound

[0046] Put 1000g of the compound of formula 1 into 7000mL of ethyl acetate and stir to dissolve it. Slowly add 240g of S-methylbenzylamine dropwise at room temperature. Solids appear continuously during the dropwise addition. Continue to stir for 1h after the dropwise addition, and obtain about 650g of the crude product by suction filtration; Put the crude product into 6500mL toluene, raise the temperature to 60-65°C, slowly add about 260-325mL of methanol under stirring, stir until completely dissolved, then slowly lower to 5-10°C, continue to stir for 2h, filter with suction, and dry the filter cake to obtain a solid 570g, the solid was recrystallized once with the toluene methanol system of the above ratio, and the obtained solid was put into 2000mL of purified water and stirred evenly, and 10% dilute phosphoric acid was added to adjust the pH to 2-3, extracted with 1500mL of ethyl acetate, and the compound of formula 2 i...

Embodiment 2

[0047] Synthesis of embodiment 2 formula 3 compound

[0048] Dissolve about 300g of the solid compound of formula 2 in 4500mL of methanol, add 150g of concentrated sulfuric acid dropwise at 0-5°C, after the drop is complete, the reaction is complete at room temperature, add 200mL of ethyl acetate and 200mL of pure water, stir, let stand and separate, and the organic layer After washing, drying and concentration, about 290 g of the compound of formula 3 was obtained as a yellow oil.

Embodiment 3

[0049] Synthesis of embodiment 3 formula 5 compound

[0050] Put 135g of L-phenylalaninol and 400g of triethylamine into a mixture of 600ml of dioxane and 400ml of pure water, and drop 200g of di-tert-butyl dicarbonate in 100mL of dioxane at 0-5°C The solution, dropwise, complete reaction at room temperature, add 400mL of dichloromethane, 200mL of pure water and stir, let it stand for stratification, wash and dry the organic phase with citric acid water, saturated sodium bicarbonate solution, pure water, and saturated brine, and concentrate to obtain The compound of formula 5 is about 205 g.

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Abstract

The invention discloses a method for synthesizing the trans hydroxyl active metabolite of loxoprofen. The present invention uses 2-[p-(bromomethyl)phenyl]propionic acid as a raw material to obtain an intermediate compound of formula 3 through resolution and methyl esterification; starting with L-phenylalaninol to prepare a chiral auxiliary compound of formula 7 The compound of cyclopentanone and chiral auxiliary formula 7 first forms Schiff base formula 9, and then condenses with intermediate formula 3 to form intermediate formula 11; the compound of intermediate formula 11 undergoes acidic hydrolysis, and stereoselectively reduces cyclopentanone carbonyl to obtain Trans hydroxyl active metabolite formula TM compound. The raw materials of this synthesis route are easy to obtain, the operation is simple, the environment is friendly, the separation method of column chromatography is avoided, and the technical requirements of industrialized large-scale production are fully satisfied.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for synthesizing a trans hydroxyl active metabolite of loxoprofen. Background technique [0002] Loxoprofen is a precursor type of phenylpropionic acid non-steroidal anti-inflammatory drugs, which is less irritating to the gastrointestinal tract after oral administration. After absorption in the body, it is biotransformed into trans-hydroxyl active metabolites by the liver. It produces pharmacological effects by inhibiting the synthesis of prostaglandins and unsaturated fatty acids through competitive binding to cyclooxygenase. In 1986, Japan's Sankyo Co., Ltd. launched Loxolo tablets and granules in Japan under the trade name of "Loxonin", and entered the Chinese market in 1995. Loxoprofen has excellent antipyretic, analgesic and anti-inflammatory effects, and its analgesic effect is 10-20 times stronger than that of ketoprofen, indomethacin, and naproxe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/373C07C51/43C07C59/54
CPCY02P20/55
Inventor 吕田王雪萌闵涛郭彦飞刘婷婷
Owner NANJING HERON PHARMA SCI & TECH CO LTD
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