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Preparation method of N-(O, O-diisopropylphosphoryl)-trans-4-hydroxy-L-proline

A technology of hydroxyproline and propylphosphoryl, which is applied in the field of pharmaceutical intermediates, can solve the problems of low product yield, waste gas generation, and many side reactions, and achieve the effects of high purity, high yield, and avoiding side reactions

Inactive Publication Date: 2018-12-28
SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method solves the problems of many side reactions, low product yield and waste gas in the traditional synthesis process, and has the advantages of few side reactions, high product yield, controllable reaction and environmental protection

Method used

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  • Preparation method of N-(O, O-diisopropylphosphoryl)-trans-4-hydroxy-L-proline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Add 174g (1.05mol) of DIPP into the 1000ml reaction flask, stir and cool down to -10°C, at this temperature, start to slowly add 455g (1.6mol) of sodium hypochlorite solution with an available chlorine content of 12.5%, and the dropping time is 60min. After the dropwise addition, continue to stir for 60 minutes at a speed of 400 r / min or more, and monitor the reaction by gas chromatography (IPC-1: DIPP<1.0%). After the reaction finishes, add sodium bisulfite 5g, measure and change color with starch-KI test paper.

[0035] Control the internal temperature at 5°C, add 100 g (0.915 mol) of L-Hyp in batches, finish adding 60 minutes, add 7.7 g of L-Hyp every 5 minutes, use 25% sodium hydroxide solution to maintain pH = 9.0 during the addition, and continue stirring for 45 minutes after adding. minute. When the pH no longer decreased, the dropwise addition was stopped, and the reaction was incubated for 30 minutes, and the reaction result was monitored by HPLC (IPC-2).

[...

Embodiment 2

[0038] Add 208g of pure water and 100g (0.915mol) of L-Hyp into a 500ml reaction bottle, cool down to 5°C, and start to add about 40.6g (0.254mol) of 25% sodium hydroxide solution dropwise under stirring. At this time, the pH=9.2, and the reaction solution is clear ,stand-by.

[0039] Add 174g (1.05mol) of DIPP into a 2000ml reaction flask, stir and cool down to -10°C, at this temperature, start to slowly add 455g (1.6mol) of sodium hypochlorite solution with an available chlorine content of 12.5%, and the dropping time is 60min. After the dropwise addition, continue to stir for 60 minutes at a speed of more than 400 r / min. The reaction was monitored by gas chromatography (IPC-1: DIPP<1.0%). After the reaction finishes, add sodium bisulfite 5g, measure and change color with starch-KI test paper.

[0040] Control the internal temperature at 0°C, add the L-Hyp aqueous solution to be used dropwise, and finish dropping after 60 minutes. During the addition, use 25% sodium hydrox...

Embodiment 3

[0043] Add 208g of pure water and 100g (0.915mol) of L-Hyp into the 2000ml reaction flask, cool down to 5°C, and start to add about 40.6g (0.254mol) of 25% sodium hydroxide solution dropwise under stirring, at this time, the pH=9.3, and the reaction solution clarify. stand-by.

[0044]Add 174g (1.05mol) of DIPP into the 1000ml reaction flask, stir and cool down to -10°C, at this temperature, start to slowly add 455g (1.6mol) of sodium hypochlorite solution with an available chlorine content of 12.5%, and the dropping time is 60min. After the dropwise addition was completed, stirring was continued for 60 minutes, and the reaction was monitored by gas chromatography (IPC-1: DIPP<1.0%). After the reaction finishes, add sodium bisulfite 5g, measure and change color with starch-KI test paper, as diisopropylphosphorous oxychloride reaction liquid.

[0045] The diisopropylphosphorous oxychloride reaction solution was kept stirring, cooled to -5°C, and the diisopropyl phosphorous ox...

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Abstract

The invention belongs to the technical field of medical intermediates and specifically relates to a preparation method of N-(O, O-diisopropylphosphoryl)-trans-4-hydroxy-L-proline. The preparation method of the N-(O, O-diisopropylphosphoryl)-trans-4-hydroxy-L-proline comprises the steps of adding L-hydroxyproline to purified water; cooling an obtained mixture; beginning to drip 25% sodium hydroxidesolution into the obtained mixture while stirring the obtained mixture; regulating pH value of a mixture to 9.0-10; stirring the mixture to a clarified state for future use; dripping sodium hypochlorite into diisopropyl phosphite at a low temperature; rapidly stirring an obtained mixture and preserving the heat of the obtained mixture for reaction; after it is detected in gas phase that DIPP reaction is completely finished, adding sodium hydrogen sulfite to a reaction product; adding prepared L-hydroxyproline solution to the reaction product; controlling the pH value of a reaction system so that the reaction system is kept to be alkaline; heating and preserving the heat of the reaction system till the pH value of a reaction liquid is not changed; using halogenated hydrocarbon to wash thereaction system and layering the reaction system; regulating an aqueous phase to be acidic by using hydrochloric acid; adding an ester organic solvent to extract the aqueous phase; decompressing and concentrating an organic phase; carrying out cooling and suction filtration on the decompressed and concentrated organic phase; and drying the cooled and sucked-filtered organic phase at 40 degrees centigrade to obtain white powder solids. The preparation method of the N-(O, O-diisopropylphosphoryl)-trans-4-hydroxy-L-proline, provided by the invention, has the advantages of less side reaction, highyield, high purity and mild reaction condition.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical intermediates, and in particular relates to a preparation method of N-(O,O-diisopropylphosphoryl)-trans-4-hydroxyl-L-proline. Background technique [0002] L-hydroxyproline (L-Hyp) was protected by diisopropyl phosphite (DIPP) to obtain N-(O, O-diisopropylphosphoryl)-trans-4-hydroxy-L-proline ( DIPP-Hyp), is an important intermediate of the side chain of ertapenem. [0003] The side chain of ertapenem is an important intermediate for the synthesis of ertapenem. According to literature reports, the side chain of ertapenem can be roughly divided into two forms with protective groups and hydrochloride. It is divided into amino protection and amino and carboxyl double protection forms, and the protecting groups are also different, mainly including allyloxycarbonyl and p-nitrobenzyloxycarbonyl, and the synthesis routes and processes of different forms of side chains are also different. Diisopr...

Claims

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Application Information

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IPC IPC(8): C07F9/572
CPCC07B2200/07
Inventor 邱化齐孙智源张林魏蒙蒙
Owner SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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