CN118684612B - A method for synthesizing a maleic polyethylene glycol drug coupling agent - Google Patents
A method for synthesizing a maleic polyethylene glycol drug coupling agentInfo
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- CN118684612B CN118684612B CN202411175014.7A CN202411175014A CN118684612B CN 118684612 B CN118684612 B CN 118684612B CN 202411175014 A CN202411175014 A CN 202411175014A CN 118684612 B CN118684612 B CN 118684612B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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Abstract
The invention relates to a synthesis method of a maleated polyethylene glycol drug coupling agent. The invention is used for solving the problems of complex synthesis process, high cost, difficult extraction and high-risk chemical agent containing of the maleic polyethylene glycol drug coupling agent in the prior art, the synthesis method of the polyethylene glycol drug coupling agent disclosed by the invention adopts a novel synthesis route, changes the synthesis sequence of functional groups, is favorable for protecting the stability of the maleic functional groups in the synthesis process and improving the purity of products, has short synthesis route and simple operation, reduces the synthesis period, thereby greatly reducing the synthesis cost, and the maleic polyethylene glycol drug coupling agent provided by the invention can change the hydrophilicity and the hydrophobicity of the maleic polyethylene glycol drug coupling agent by changing the length of a carbon chain and polyethylene glycol, thereby being better used for coupling drugs and bioactive molecules and linking other substances, and greatly improving the application range of the maleic polyethylene glycol drug coupling agent.
Description
Technical Field
The invention relates to a preparation technology of a drug coupling agent, in particular to a synthesis method of a maleated polyethylene glycol drug coupling agent.
Background
Polyethylene glycol has excellent water solubility, compatibility, lubricity, adhesiveness and thermal stability, and the product is nontoxic and nonirritating, so that the polyethylene glycol has been widely applied to medicines. For example, the pharmaceutical composition can be used as a solvent for injection medicines, an excipient and a modifier for tablets, and can be used for treating diseases by combining polyethylene glycol interferon and medicines clinically. With the development of biotechnology, protein biological drugs are being developed and applied more and more widely due to the advantages of high activity, strong specificity, clear biological function, low toxicity and the like. However, problems such as short half-life, poor stability, poor water solubility, immunogenicity, rapid renal clearance, etc., limit their further development. In order to solve these problems, researchers have made various attempts, and polyethylene glycol modification of protein drugs is one of the most important chemical modification techniques.
With the development of biotechnology, protein biological drugs are being developed and applied more and more widely due to the advantages of high activity, strong specificity, clear biological function, low toxicity and the like. The development of polyethylene glycol derivatives has undergone a first generation of random modifications, a second generation of specific and functional modifications, and the use of third generation branched structures. The polyethylene glycol modifier is improved and innovated continuously and linked specifically with different medicines. Its application also extends from simple drug modification to biosensing, drug delivery, etc.
The maleated polyethylene glycol drug coupling agent has the following effects that 1, the maleated polyethylene glycol drug coupling agent can be used for coupling drugs with bioactive molecules (such as antibodies, polypeptides and the like) to form drug-conjugates, the conjugates can realize directional delivery and release in vivo, improve the therapeutic effect of the drugs and reduce side effects, 2, the maleated polyethylene glycol drug coupling agent can be used for modifying the surface of biological materials (such as biosensors, biochips and the like) to improve the biocompatibility and stability, 3, the cross-linking of the polymers can be realized by reacting maleated imide groups with thiol or amino groups in the polymers, the mechanical property, the thermal stability and the chemical stability of the polymers can be improved, 4, the cross-linking agent can be used for modifying the surface properties of the high polymer materials, such as hydrophilicity, hydrophobicity, biocompatibility and the like, the application performance of the high polymer materials can be changed, and the application fields of the high polymer materials can be expanded.
The coupling agent has wide application in various fields, and the diversity of the coupling target requires the diversification of the structure of the coupling agent. In recent years, many of these coupling agents have been studied, such as route one,
In the process of the first synthesis route, sodium azide is a highly toxic reagent, and meanwhile, the sodium azide is an explosive high-risk product, so that the limitation exists in the industrial production process;
In the second route, the first route is used for the first route,
In the second route, hydrazine hydrate which is easy to explode is used in the synthesis process, and meanwhile, solid impurities are excessive and difficult to purify during amino synthesis, and meanwhile, the cost of the used raw materials is high.
In summary, the existing synthetic maleic polyethylene glycol drug coupling agent has the defects of complex process, high cost, difficult extraction, high-risk chemical agent and the like. Based on the above situation, the invention provides a novel synthesis method of the coupling agent of the polyethylene glycol maleate medicine, which can effectively solve the problems.
Disclosure of Invention
The invention provides a synthesis method of a maleated polyethylene glycol drug coupling agent, which solves the problems of complex synthesis process, high cost, difficult extraction and high-risk chemical agent content of the maleated polyethylene glycol drug coupling agent in the prior art.
The technical problems are mainly solved by the following technical scheme that the synthesis method of the coupling agent for the maleated polyethylene glycol medicine comprises the following steps:
S1, adding Cbz-NH (CH 2) mCOOH and dichloromethane into a reactor, sequentially adding EDCI and NH2-PEGn-CH2CH2COOtBu, then preserving the temperature of the whole reaction system, determining a reaction end point through a TLC point plate, and obtaining Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOtBu through an extraction and washing process of the reaction system;
s2, placing Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOtBu into a reactor, adding dichloromethane and trifluoroacetic acid in a volume ratio of 1-2:1, then preserving the temperature of the whole reaction system, determining a reaction end point through a TLC (thin layer chromatography) point plate, and treating the reaction system through an acid-base method to obtain Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOH;
S3, adding Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOH into a hydrogenation reactor, adding methanol for dissolution, adding 2-10% palladium-carbon catalyst, introducing hydrogen, and ending the reaction when the hydrogen is not consumed any more;
S4, under the nitrogen atmosphere, placing NH2 (CH 2) mCONH-PEGn-CH2CH2COOH and maleic anhydride into a reactor, adding glacial acetic acid for reflux reaction, spin-drying the glacial acetic acid in a reduced pressure environment to obtain a crude product, and purifying and weighting crystallization of the crude product by a column to obtain white solid powder Mal- (CH 2) mCONH-PEGn-CH2CH2COOH;
S5, placing Mal- (CH 2) mCONH-PEGn-CH2CH2COOH and N, N '-disuccinimidyl carbonate into a reactor, adding methylene dichloride for dispersion, adding a catalyst DMAP, then carrying out heat preservation on the whole reaction system, determining the end point of the reaction by a TLC (thin layer chromatography) point plate, filtering the reaction liquid to remove unreacted N, N' -disuccinimidyl carbonate, flushing a filter cake with 50ml of methylene dichloride, collecting filtrate, and obtaining white solid powder Mal- (CH 2) mCONH-PEGn-CH2CH2COONHS by extraction and crystallization.
Cbz shown in the above synthetic method is benzyloxycarbonyl, mal is maleimide, NHS is N-hydroxysuccinimide, the following formula of the synthetic route of the maleated polyethylene glycol drug coupling agent disclosed in the invention,
The invention mainly relates to synthesis of Mal- (CH 2) mCONH-PEGn-CH2CH2COONHS compounds, wherein n is the number of ethylene glycol, m is the number of carbon chains, and m=an integer of 1-5.
The synthetic method of the coupling agent of the maleic polyethylene glycol medicine adopts a new synthetic route, changes the synthetic sequence of the functional groups, is beneficial to protecting the stability of the maleic functional groups in the synthetic process and improving the purity of the product. Compared with the existing synthetic route, the method has the advantages of short synthetic route, simple operation and reduced synthetic period, thereby greatly reducing the synthetic cost. The scheme disclosed by the invention avoids the extremely toxic and explosive sodium azide in the first route, improves the production safety and the yield, and simultaneously avoids the problems that the hydrazine hydrate which is easy to explosion is used in the synthesis process of the second route, and the solid impurities are too much to purify and the cost of the used raw materials is high when amino is synthesized.
Further, in S1, the molar ratio of the NH2-PEGn-CH2CH2COOtBu, the EDCI and the Cbz-NH (CH 2) mCOOH is 1:1.05-1.5:1.05-1.5, the reaction temperature is kept between 0 and 25 ℃, and the heat preservation time is 2 to 6 hours.
Further, in S2, the ratio of Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOtBu, dichloromethane and trifluoroacetic acid is=1 mmol:1ml:1ml, the reaction temperature is kept between 0 ℃ and 25 ℃, and the heat preservation time is 2-6 hours.
Further, in S3, the mass ratio of the Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOH to the palladium-carbon catalyst is 1:0.01-0.1, and the reaction temperature is kept between 25 ℃ and 55 ℃.
Further, in S4, the molar ratio of the NH2 (CH 2) mCONH-PEGn-CH2CH2COOH to the maleic anhydride is 1:1.0-1.2, the reaction temperature is kept between 110 ℃ and 120 ℃, and the reaction time is 4-6 hours.
Further, in S5, the mol ratio of the Mal- (CH 2) mCONH-PEGn-CH2CH2COOH, the N, N' -disuccinimidyl carbonate and the DMAP is 1:1.05-1.2:0.03-0.05, the reaction temperature is kept between 5 ℃ and 25 ℃, and the reaction time is 2-8 hours.
Compared with the prior art, the invention has the characteristics that 1. The synthesis method of the polyethylene glycol drug modifier adopts a new synthesis route, changes the synthesis sequence of the functional groups, is favorable for protecting the stability of the maleic functional groups in the synthesis process and improving the purity of products, has short synthesis route and simple operation, reduces the synthesis period, and thus greatly reduces the synthesis cost;
2. the maleic polyethylene glycol drug coupling agent provided by the invention can change the hydrophilicity and the hydrophobicity of the maleic polyethylene glycol drug coupling agent by changing the length of the carbon chain and the polyethylene glycol, so that the maleic polyethylene glycol drug coupling agent is better used for coupling a drug with a bioactive molecule and linking other substances, and the application range of the maleic polyethylene glycol drug coupling agent is greatly improved.
Drawings
FIG. 1 is a HNMR diagram of the coupling agent Mal- (CH 2) 2CONH-PEG4-CH2CH2 COOH;
FIG. 2 is a HNMR diagram of the coupling agent Mal- (CH 2) 2CONH-PEG4-CH2CH2 COONHS;
FIG. 3 is a HNMR diagram of the coupling agent Mal- (CH 2) 2CONH-PEG8-CH2CH2 COOH;
FIG. 4 is a HNMR of the coupling agent Mal- (CH 2) 2CONH-PEG8-CH2CH2 COONHS.
Detailed Description
The technical scheme of the invention is further specifically described below through examples and with reference to the accompanying drawings.
EXAMPLE 1S 1, cbz-NH (CH 2) 2COOH (24.5 g, 0.11 mol) and 200 ml of dichloromethane were added to a 500ml reactor, EDCI (23.0 g, 0.12 mol) and NH2-PEG4-CH2CH2COOtBu (32.1 g, 0.1 mol) were sequentially added, the reaction system was incubated for 4 hours at 5℃and the end point of the reaction was determined by TLC spot plate, then the reaction solution was transferred to a separating funnel, and after 30 ml of water was added, the aqueous sodium bicarbonate solution was washed once, the organic phase was dried with anhydrous magnesium sulfate, concentrated, and dried to obtain Cbz-NH (CH 2) 2CONH-PEG4-CH 2COOtBu 50.6 g with a purity of 98.3% (yield 96.2%) which was directly used for the next step of synthesis;
S2, weighing Cbz-NH (CH 2) 2CONH-PEG4-CH2CH2COOtBu (42.1 g, 0.08 mol), placing into a 250ml reactor, adding 80ml of dichloromethane and 80ml of trifluoroacetic acid, keeping the temperature of a reaction system at 15 ℃ and reacting for 4 hours, determining a reaction end point through a TLC (thin layer chromatography) spot plate, diluting the reaction system with 200ml of dichloromethane, washing with 80ml of clear water for 5-6 times, carrying out spin drying on an organic phase to obtain a crude product, adding 200ml of alkaline water for dissolving, washing with 50ml of ethyl acetate for 3 times, washing impurities, adjusting the pH of the water phase by hydrochloric acid=4, extracting the product with 100ml of dichloromethane for three times, collecting a dichloromethane phase, washing with 100ml of clear water once, drying the dichloromethane phase and concentrating to obtain Cbz-NH (CH 2) 2CONH-PEG4-CH 2COOH 34.6 g, wherein the purity is 98.5% (the yield is 92 percent);
S3, weighing Cbz-NH (CH 2) 2CONH-PEG4-CH2CH2COOH (32.9 g, 0.07 mol), adding 150ml of methanol into a hydrogenation reactor for dissolution, adding palladium-carbon catalyst, introducing hydrogen into the reaction system for reaction at 35 ℃, and finishing the reaction when the hydrogen is not consumed any more;
S4, referring to FIG. 1, under the nitrogen atmosphere, weighing NH2 (CH 2) 2CONH-PEG4-CH2CH2COOH (23.5 g, 0.07 mol) and maleic anhydride (6.9 g, 0.07 mol), putting into a 250ml reactor, adding 100ml of glacial acetic acid for reflux reaction for 4 hours, spinning the reaction liquid under reduced pressure to obtain a crude product, purifying the crude product by a column to aggravate crystallization to obtain white solid powder Mal- (CH 2) 2CONH-PEG4-CH2CH2COOH 13.4 g, wherein the purity is 98.7% (the yield is 46 percent);
S5, see FIG. 2, mal- (CH 2) 2CONH-PEG4-CH2CH2COOH (10.4 g, 0.025 mol) and N, N '-disuccinimidyl carbonate (7.7 g, 0.03 mol) were weighed into a 250ml reactor, 100ml methylene chloride was added to disperse, DMAP (0.15 g, 1.3 mmol) was added as a catalyst, the reaction system was kept at 15℃for 3 hours, the endpoint of the reaction was determined by a spot plate, the reaction solution was filtered to remove unreacted N, N' -disuccinimidyl carbonate, the filter cake was washed with 50ml methylene chloride, the filtrate was collected and transferred into a separating funnel, washed with 50ml clean water 3 times, 50ml aqueous sodium chloride was washed once, the organic phase was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was recrystallized by ethyl acetate/petroleum ether=7/3 to obtain white solid powder Mal- (CH 2) 2 PEG4-CH2CH2 COONHS.5.99.5.5% pure 90% (purity: 621%).
EXAMPLE 2S 1, cbz-NH (CH 2) 2COOH (49.1 g, 0.22 mol) and 400 ml of dichloromethane were added to a 1000ml reactor, EDCI (23.0 g, 0.24 mol) and NH2-PEG8-CH2CH2COOtBu (99.4 g, 0.2 mol) were then added sequentially, the reaction system was incubated for 5℃for 4 hours, the end point of the reaction was determined by TLC spot plate, then the reaction solution was transferred to a separating funnel, and after 100ml of water was added for two times, 100ml of aqueous sodium bicarbonate was washed once, the organic phase was dried with anhydrous magnesium sulfate, concentrated, and dried to obtain Cbz-NH (CH 2) 2CONH-PEG8-CH 2COOtBu133.4 g with a purity of 98.8% (yield 95.0%) which was directly used for the next step of synthesis;
S2, weighing Cbz-NH (CH 2) 2CONH-PEG8-CH2CH2COOtBu (70.2 g,0.1 mol), putting into a 500ml reactor, adding dichloromethane/trifluoroacetic acid=100 ml/100ml, then carrying out heat preservation on a reaction system for 15 ℃ for 4 hours, determining a reaction end point through a TLC spot plate, diluting the reaction system by adding 200ml dichloromethane, washing with 100ml of clear water for 5-6 times, carrying out organic phase spin drying to obtain a crude product, adding 500ml of alkaline water for dissolving, washing with 100ml of ethyl acetate for 3 times, washing impurities, adjusting the pH value of the water phase by hydrochloric acid=4, extracting the product with 150ml of dichloromethane for three times, collecting a dichloromethane phase, washing once with 100ml of clear water, drying the dichloromethane phase, and concentrating to obtain Cbz-NH (CH 2CONH-PEG8-CH2CH2COOH 60.1 g, wherein the purity is 98.7% (the yield is 93 percent);
S3, weighing Cbz-NH (CH 2) 2CONH-PEG8-CH2CH2COOH (51.7 g,0.08 mol), adding 250ml of methanol into a hydrogenation reactor for dissolution, adding a palladium-carbon catalyst, introducing hydrogen, reacting the reaction system at 35 ℃, and finishing the reaction when the hydrogen is not consumed any more;
S4, referring to FIG. 3, under the protection of nitrogen, weighing NH2 (CH 2) 2CONH-PEG8-CH2CH2COOH (41.0 g,0.08 mol) and maleic anhydride (7.8 g,0.08 mol) into a 250ml reactor, adding 100ml of glacial acetic acid for reflux reaction for 4 hours, spin-drying the reaction liquid under reduced pressure to obtain a crude product, purifying the crude product by a column to aggravate crystallization to obtain white solid powder Mal- (CH 2) 2CONH-PEG8-CH2CH2COOH 21.3 g, wherein the purity is 98.5% (the yield is 45 percent);
S5, see FIG. 4, mal- (CH 2) 2CONH-PEG8-CH2CH2COOH (21.3 g,0.036 mol) and N, N '-disuccinimidyl carbonate (11.0 g,0.043 mol) were weighed into a 500ml reactor, 150ml methylene chloride was added to disperse, the reaction system was incubated at 15℃for 4 hours with the addition of DMAP (0.22 g, 1.8 mmol), the endpoint of the reaction was determined by a spot plate, the reaction solution was filtered to remove unreacted N, N' -disuccinimidyl carbonate, the filter cake was washed with 100ml methylene chloride, the filtrate was collected and transferred into a separating funnel, washed with 50ml clean water 3 times, 50ml aqueous sodium chloride was washed once, the organic phase was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was recrystallized and purified by ethyl acetate/petroleum ether=4/1 to obtain white solid powder Mal- (CH 2) 2 PEG8-CH2CH2COONHS 22.6.6. 22.6 g% with a purity of 91%.
It will be obvious to those skilled in the art that the present invention may be varied in a number of ways without departing from the scope of the invention. All such modifications as would be obvious to one skilled in the art are intended to be included within the scope of this claims.
Claims (5)
1. The synthesis method of the maleated polyethylene glycol drug coupling agent is characterized by comprising the following steps:
S1, adding Cbz-NH (CH 2) mCOOH and dichloromethane into a reactor, sequentially adding EDCI and NH2-PEGn-CH2CH2COOtBu, then preserving the temperature of the whole reaction system, determining a reaction end point through a TLC point plate, and obtaining Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOtBu through an extraction and washing process of the reaction system;
s2, placing Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOtBu into a reactor, adding dichloromethane and trifluoroacetic acid in a volume ratio of 1-2:1, then preserving the temperature of the whole reaction system, determining a reaction end point through a TLC (thin layer chromatography) point plate, and treating the reaction system through an acid-base method to obtain Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOH;
S3, adding Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOH into a hydrogenation reactor, adding methanol for dissolution, adding a palladium-carbon catalyst, and introducing hydrogen, and ending the reaction when the hydrogen is not consumed any more;
S4, under the nitrogen atmosphere, placing NH2 (CH 2) mCONH-PEGn-CH2CH2COOH and maleic anhydride into a reactor, adding glacial acetic acid for reflux reaction, spin-drying the glacial acetic acid in a reduced pressure environment to obtain a crude product, and purifying and weighting crystallization of the crude product by a column to obtain white solid powder Mal- (CH 2) mCONH-PEGn-CH2CH2COOH;
S5, placing Mal- (CH 2) mCONH-PEGn-CH2CH2COOH and N, N ' -disuccinimidyl carbonate into a reactor, adding dichloromethane for dispersion, adding a catalyst DMAP, then carrying out heat preservation on the whole reaction system, determining the end point of the reaction by a TLC (thin layer chromatography) point plate, filtering the reaction liquid to remove unreacted N, N ' -disuccinimidyl carbonate, flushing a filter cake by 50ml of dichloromethane, collecting filtrate, and carrying out extraction washing and crystallization to obtain white solid powder Mal- (CH 2) mCONH-PEGn-CH2CH2COONHS, wherein the molar ratio of the Mal- (CH 2) mCONH-PEGn-CH2CH2COOH to the N, N ' -disuccinimidyl carbonate to the DMAP is 1:1.05-1.2:0.03-0.05, and the reaction temperature is kept between 5 and 25 ℃, and the reaction time is 2-8 hours.
2. The method for synthesizing the maleic polyethylene glycol drug coupling agent according to claim 1, wherein in S1, the molar ratio of NH2-PEGn-CH2CH2COOtBu, EDCI and Cbz-NH (CH 2) mCOOH is 1:1.05-1.5:1.05-1.5, the reaction temperature is kept between 0-25 ℃, and the heat preservation time is 2-6 hours.
3. The method for synthesizing the maleic polyethylene glycol drug coupling agent according to claim 1, wherein in S2, the ratio of Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOtBu, dichloromethane and trifluoroacetic acid is=1 mmol:1ml:1ml, the reaction temperature is kept between 0 ℃ and 25 ℃, and the heat preservation time is 2-6 hours.
4. The method for synthesizing the maleic polyethylene glycol drug coupling agent according to claim 1, wherein in S3, the mass ratio of the Cbz-NH (CH 2) mCONH-PEGn-CH2CH2COOH to the palladium-carbon catalyst is 1:0.01-0.1, and the reaction temperature is kept between 25 ℃ and 55 ℃.
5. The method for synthesizing the maleic polyethylene glycol drug coupling agent according to claim 1, wherein in S4, the molar ratio of NH2 (CH 2) mCONH-PEGn-CH2CH2COOH to maleic anhydride is 1:1.0-1.2, the reaction temperature is kept between 110 ℃ and 120 ℃, and the reaction time is 4-6 hours.
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