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A kind of preparation method of mpeg2000-dspe sodium salt

A technology of sodium salt and compound, applied in the field of preparation of mPEG2000-DSPE sodium salt, can solve the problems of difficult purification, difficult industrial production, many side reactions, etc., so as to reduce the reaction risk and cost, and reduce the generation and reaction of impurities. Highly selective effect

Active Publication Date: 2015-09-09
苏州东南药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to provide a kind of 1,2-distearoyl-s -A new preparation method of glycerol-3-phosphatidylethanolamine-N-[methoxyl (polyethylene glycol)-2000] sodium salt; this method can amplify the production of MPEG-2000-DSPE sodium salt, and promote it to the market And more and better development of new domestic preparations to provide high-quality pharmaceutical excipients provides a new and feasible industrial production route

Method used

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  • A kind of preparation method of mpeg2000-dspe sodium salt
  • A kind of preparation method of mpeg2000-dspe sodium salt
  • A kind of preparation method of mpeg2000-dspe sodium salt

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Effect test

Embodiment 1

[0027] Embodiment 1. The preparation of compound compound IV:

[0028] Dissolve 0.73g of ethanolamine in 100ml of chloroform, and slowly add 21.5g (0.01mol) of mPEG-2000-Su (compound VII) 100ml of chloroform solution to the above reaction solution dropwise at room temperature, after the addition is complete, stir at room temperature for reaction 4 -6 hours; the reaction solution was evaporated to dryness, 200 ml of n-hexane was added to the residue, beating at room temperature for 1 hour, suction filtration, and the filter cake was recrystallized with ethyl acetate to obtain 18.5 g of white solid, TLC (GF254) single spot.

[0029] 1 HNMR (500Hz, DMSO-d6): 4.20-4.30 (m, 2H), 3.50-3.84 (m, 180H), 3.30-3.45 (m, 3H).

Embodiment 2

[0030] Embodiment 2. Preparation of compound compound V:

[0031] Dissolve 62.5g (0.1mol) of compound I in 1500ml of dichloromethane, cool down to 0-5°C, and under the protection of argon, slowly add 33.8g (0.1mol) of compound II and 1-H-tetra Nitrazole 7g (0.1mol), temperature control 0-5 ℃ stirring reaction for 2-4 hours; under the above reaction conditions, add 204g (0.1mol) compound IV and 1-H-tetrazolium to the above reaction solution in sequence 7g (0.1mol), temperature controlled at 0-5°C and stirred for 2-4 hours; the reaction solution was cooled to -20~-15°C, and mCPBA (m-chloroperoxybenzoic acid) 304g (0.15 mol), temperature controlled and stirred for 30 minutes; lower the temperature of the reaction solution to -30~-20°C, slowly add 12.6g (0.1mol) sodium sulfite / 30ml purified aqueous solution dropwise to the reaction solution, and naturally rise to room temperature and stir for 45 minutes Starch-KI test paper test reaction solution does not turn blue, the reaction ...

Embodiment 3

[0034] The preparation of embodiment 3.MPEG-2000-DSPE (non sodium):

[0035] Compound V refined product 28.7g (0.01mol) is dissolved in 287ml dehydrated alcohol, adds 5% palladium carbon 2.87g (10%) and solid ammonium carbonate 2.88g (0.03mol) successively in the reaction solution, temperature control 25- Stir and react at 40°C for 4-6 hours, filter to remove solid insoluble matter, cool the filtrate to 0-5°C to crystallize, filter with suction, wash the filter cake with cold absolute ethanol, and dry under vacuum at room temperature to obtain 23.5g of white solid, TLC (GF254) single point.

[0036] 31 PNMR (500Hz, D2O): 2.345

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Abstract

The invention discloses a preparation method of mPEG2000-DSPE sodium salt, which comprises the following steps of: reacting a compound I with a compound II so as to obtain a compound III; reacting a compound VII with ethanolamine so as to obtain a compound IV; and then reacting the compound III with the compound IV so as to obtain a compound V; removing benzyl protecting groups in the compound V by using palladium on activated carbon and ammonium carbonate so as to obtain a compound VI; and finally, reacting the compound VI with alkali. The method is less in process steps, an operation of preparing the compound V by using the compound I can be completed through a one-pot reaction, so that the technological operation is simple, and an effect of industrial production is easily achieved; and a situation of taking DSPE as an intermediate is avoided, thereby reducing the production of impurities and improving the overall yield; and the reaction selectivity is high, the occurrence of side reactions and by-products is reduced, and the risk and cost of reaction are lowered.

Description

technical field [0001] The invention relates to a long-circulation liposome phospholipid pharmaceutical excipient—1,2-distearoyl-s-glycerol-3-phosphatidylethanolamine-N-[methoxyl (polyethylene glycol)-2000] New and efficient preparation of sodium salts. Background technique [0002] Phospholipids are an important part of biological membranes. Their inherent amphiphilic properties, which are both hydrophilic and lipophilic, enable phospholipids to spontaneously form closed bilayers in aqueous media and become the skeleton of biological membranes. Utilize this property to develop a new type of pharmaceutical preparation technology - liposome. Liposomes were first discovered by British scholar Bangham when phospholipids were dispersed in water and observed under an electron microscope. In 1971, British Lyman et al. used liposomes as drug carriers. Phospholipids play a vital role in liposome technology, and its development has gone through three generations: the first generati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48A61K47/34
Inventor 吉民李锐马俊海
Owner 苏州东南药业股份有限公司
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