CN112608364B - Pectin-doxorubicin conjugate and preparation method of intermediate thereof - Google Patents
Pectin-doxorubicin conjugate and preparation method of intermediate thereof Download PDFInfo
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Abstract
The present invention relates to a process for the preparation of pectin-doxorubicin conjugates and intermediates thereof. The technical scheme of the invention improves the purity and the total yield of the small molecular compound for synthesizing the intermediate by redesigning the integral route for synthesizing the important intermediate of the pectin-adriamycin conjugate, and has the advantages of high yield, simple and convenient post-treatment and easy purification; simultaneously saves two expensive important raw materials Fmoc-NH-PEG 8 The consumption of the-COOH and the doxorubicin is reduced, the consumption of other reagents is reduced, the cost is greatly reduced, the efficiency is improved, the generation of waste is reduced, the environment is protected, and the method is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of medicine preparation methods, in particular to a preparation method of pectin-doxorubicin conjugate and an intermediate thereof.
Background
The pectin-doxorubicin conjugate targeted drug delivery system (PAC) is based on a great deal of previous work and literature research, pectin is selected as a carrier of a high-molecular anticancer prodrug, and the structure of the pectin is modified so that the pectin can be covalently combined with polypeptide-doxorubicin to form a water-soluble pectin-doxorubicin conjugate with high drug loading capacity.
PAC is a polymer conjugate, the particle size is about 200nm, and part of drugs entering the circulatory system after injection can be accumulated in tumor tissues by utilizing the permeation enhancement and retention Effect (EPR) of the tumor tissues on the macromolecular substances, so that the purpose of passive targeting is achieved. PAC is gradually phagocytized by tumor cells in tumor tissues, and water in lysosomes is interpreted to release doxorubicin, which plays a role in killing tumors. The patent application with the application number of CN201910524576.0 discloses a pectin-adriamycin conjugate, which solves the problem of poor anti-tumor curative effect caused by indissolvable pectin and adriamycin directly bonded through amide bonds or acylhydrazone bonds, but the disclosed production process has a plurality of problems such as low total yield, difficult post-treatment, great obstacle to large-scale production and the like. The production process comprises grafting doxorubicin onto Fmoc-Val-Ala-PABC (in practice Fmoc-Val-Ala-PABC-PNPO) intermediate to obtain important intermediate Fmoc-Val-Ala-PABC-DOX, and removing fluorenylmethoxycarbonyl protecting group to obtain Val-Ala-PABC-DOX and Fmoc-NH-PEG 8 condensing-COOH to obtain Fmoc-NH-PEG 8 -CO-Val-Ala-PABC-DOX. Two problems of great difficulty and serious defects of the process are encountered in the process: 1) The removal of the fluorenylmethoxycarbonyl protecting group (Fmoc) is not easy to amplify, the basic amino group after the removal of the protecting group is easy to react with doxorubicin, the process is difficult to control, and the product is not easy to purify; 2) Val-Ala-PABC-DOX and Fmoc-NH-PEG 8 The reaction conversion rate of the condensation of-COOH is low, more byproducts are generated, column chromatography (almost no adsorption tail can be solved by normal phase system column chromatography) is needed in the treatment and purification process, and the separation is difficult and the yield is low.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of pectin-adriamycin conjugate and an intermediate thereof, wherein the preparation method has the advantages of high yield, simple and convenient post-treatment, low production cost, environmental protection and suitability for large-scale production.
The technical scheme adopted by the invention for achieving the purpose is as follows: a method of preparing a pectin-doxorubicin conjugate intermediate having a structure according to formula (I):
b-c-d-e(I)
in the formula (I), the main structure of b is PEG n C is an enzymatic cleavage group, polypeptide or polypeptide derivative, d is a self-degrading group, e is doxorubicin DOX;
the pectin-doxorubicin conjugate drug has the structure: polymer-peptide linker-doxorubicin conjugated drug a-b-c-d-e, wherein polymer a is preferably pectin;
the specific steps of the optimized preparation method of the peptide linker intermediate b-c-d-e of the polymer-based doxorubicin conjugated drug are as follows:
1) Preparing Fmoc-b-c-d-e from Fmoc-b-c-d;
2) Removing Fmoc protecting group in the presence of non-nucleophilic alkaline reagent to obtain b-c-d-e.
Further, in the formula (I), n is an integer of 1-20, and c is any one of dipeptide, dipeptide derivative, tripeptide derivative, tetrapeptide or tetrapeptide derivative;
further, n is an integer of 6 to 12; still more preferably, n is 8;
further, c is Val-Ala;
further, d represents, in the case of direct connection to e, an aminobenzyloxycarbonyl group which is a self-degrading group;
further, d, if not attached to e, may represent an aminobenzyloxycarbonyl group which is a self-degrading group attached to a protecting group; still more preferably, the aminobenzyloxycarbonyl group is p-aminobenzyloxycarbonyl, i.e. PABC.
Further, the non-nucleophilic alkaline reagent is DBU;
further, b is linked to c through a carbonyl group to form an amide bond; still more preferably, PEG 8 Through an additional carbonyl group to form an amide bond with c;
further, b is linked to Fmoc by an amino group to form an amide bond; still more preferably, PEG 8 An amide bond with Fmoc via an additional amino group;
still further, b is NH 2 -PEG n -CO-。
Further, the specific steps are as follows:
1) From Fmoc-NH-PEG 8 -CO-Val-Ala-PABC without or with Fmoc-NH-PEG 8 CO-Val-Ala-PABC-PNPO preparation of-NH-PEG 8 -CO-Val-Ala-PABC-DOX, PNPO representing p-nitrophenoxy;
2) Fmoc-NH-PEG in the presence of DBU 8 Deprotection of the-CO-Val-Ala-PABC-DOX to give NH 2 -PEG n -CO-Val-Ala-PABC-DOX。
Further, fmoc-NH-PEG 8 The reaction of-CO-Val-Ala-PABOH with DPNP in the presence of DIEA to produce Fmoc-NH-PEG 8 -CO-Ala-PABC-PNPO, DPNP is di (p-nitrophenyl) carbonate.
Further, val-Ala-PABOH and Fmoc-NH-PEG 8 Fmo-NH-PEG is prepared by the reaction of-COOH 8 -CO-Val-Ala-PABOH。
Further, val-Ala-PABOH is prepared by removing Fmoc protecting group from Fmoc-Val-Ala-PABOH in the presence of DEA.
Further, the specific steps are as follows:
further, the Fmoc-NH-PEG 8 the-COOH structure is shown below:
the invention also provides a preparation method of the pectin-adriamycin conjugate, which is characterized in that the compound of the formula (13) and NH prepared by the preparation method 2 -PEG 8 -CO-Val-Ala-PABC-DOX in the presence of an alkaline agent to prepare pectin-doxorubicin conjugate,
in the formula (13), a is an integer selected from 2-4, and m is 1-60KD.
The invention has the advantages and effects that:
1) The route basically solves a large number of problems existing before, can realize feasibility and controllability of the synthesis process of related steps, firstly, improves the total yield of the synthesized small molecular compounds from 1.9% to 20.1% by redesigning the whole route of the synthesized small molecular compounds, and basically solves the technical problems which can not be solved by normal phase system column chromatography and the like existing before almost can not be solved by adsorption tailing and the like; and secondly, the Fmoc is removed by adopting the DBU which is an excellent non-nucleophilic alkaline organic reagent, so that a better effect is obtained, a great breakthrough is made compared with the prior process, and the milligram-scale amount obtained by one-time preparation is successfully amplified to gram-scale, so that the method is more beneficial to large-scale production.
2) The method solves the serious problems of low yield and difficult post-treatment in the prior process. Simultaneously saves two expensive important raw materials Fmoc-NH-PEG 8 The consumption of the-COOH and the doxorubicin is reduced, the consumption of other solvent reagents is reduced, the cost is greatly reduced, the efficiency is improved, the generation of waste is reduced, the environment is protected, and the production process is more similar.
Drawings
FIG. 1 for NH preparation 2 -PEG 8 -CO-Val-Ala-PABC-DOX process scheme.
Detailed Description
The present invention will be further specifically described by the following examples, which are not intended to limit the present invention in any way.
Example 1
Compound 1 (100 g,0.2946 mol) was dissolved in 1LTHF, NHS (37.2 g,0.3231 mol) and DCC (86 g,0.4175 mol) were added sequentially and stirred at room temperature for 4 hours to complete the reaction. The white solid was removed by filtration, the filter cake was washed with THF (100 ml x 4), the filtrate was collected, the filtrate was concentrated in vacuo to give a crude yellow gum, the crude was slurried with 200ml petroleum ether to precipitate a white solid, the solid was completely dispersed, filtered off with suction, and the filter cake was washed with petroleum ether (50 ml x 4) to give 134g of white solid compound in 98% yield.
Example 2
The Fmoc-Val-OSu (134 g,0.307 mol) was dissolved in 1.35L THF, L-alanine (29.2 g,0.3277 mol), naHCO were added sequentially 3 (27.3g，0.3277mol)、425ml H 2 O. Stirring at room temperature for 27h, and monitoring the reaction. Concentrating under vacuum to remove THF, adding water (2L) for dilution, adjusting pH to 3 with HCl solution (2 mol/ml), precipitating solid, pulping overnight, vacuum filtering, filtering cake with H 2 O (100 ml. Times.4) to obtain crude S3. Crude S3 was slurried with EA: pe=1:3 (1.45L) for 1h, suction filtered and cake EA: PE 1:3 (200 ml x 4) washed. 114.5g of a white solid compound (Fmoc-type)Val-Ala-OH), yield 91%.
Example 3
Fmoc-Val-Ala-OH (82.52 g,0.2015 mol) was added to the flask, 982ml DCM was added as a suspension, 4-aminobenzyl alcohol (30.24 g, 0.2455mol), EEDQ (74.27 g,0.30033 mol) and finally 512ml methanol were added until the solution was clear, reacted at room temperature for 5 hours, suction filtered to give a white solid, which was washed with DCM (100 ml. Times.3). The filtrate was collected, the DCM was spun off under reduced pressure and the remaining solid was slurried 2 times, washed with DCM (50 ml x 3) to give a white solid. The two white solids were combined, washed with DCM (200 ml x 2), filtered and dried under vacuum at ambient temperature to give 60.1g of the white solid product (Fmoc-Val-ALa-PABOH) in 57% yield.
Example 4
Fmoc-Val-Ala-PABOH (20 g,0.03879 mol) was added to the flask, dissolved in 50ml DMF, 20ml DCM was added, DEA (3.9959 ml,0.03879 mol) was added, and the reaction was carried out at room temperature for 2 hours. Petroleum ether: the reaction liquid is extracted for 8 times by a solution of methylene dichloride (10:1) to obtain a pure yellow colloidal compound Val-Ala-PABCOH. The product was purified with 40ml MeOH: DCM (1:1) was dissolved and transferred to a round bottom flask and the remaining diethylamine was removed by rotary evaporation at 40 ℃. 10.5g of yellow colloidal compound (Val-Ala-PABOH) was obtained in 92% yield.
Example 5
Fmoc-NH-PEG was weighed 8 -COOH (1.738 g,2.6214 mmol), dissolved in 8ml DCM in a reaction flask, HATU (1.396 g,3.6715 mmol) was added, val-Ala-PABOH (1 g,3.4088 mmol) dissolved in 7ml DCM in a reaction flask, ice-bathDIPEA (685 ul,3.9328 mmol) was added after 10 minutes, and the reaction was resumed at room temperature for 6 hours after stirring in an ice bath for 10 minutes. The reaction was filtered, washed with DCM (5 ml x 3) and the filtrate was collected. The filtrate was washed with ph=3 hydrochloric acid solution (30 ml×3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the solid was washed with DCM (10 ml×3). The solvent was removed under reduced pressure at 30℃and then dried under vacuum with an oil pump to give 2.678g of a yellow colloidal compound (Fmoc-PEG) 8 -CO-Val-Ala-PABOH) in 84% yield.
Example 6
Fmoc-NH-PEG 8 CO-Val-Ala-PABOH (15.66 g,0.01668 mol) was dissolved in the reaction tube with 110ml DCM, after 10 minutes in ice water, bis (p-nitrophenyl) carbonate (7.3 g,0.02668 mol) was added followed by DIPEA (6.54 ml, 0.041696 mol) and the reaction was allowed to resume at room temperature overnight after stirring in ice bath for 10 minutes. The reaction was washed with aqueous sodium carbonate at ph=9 (100 ml×3), then with aqueous hydrochloric acid at ph=3 (100 ml×3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the solid was washed with DCM (10 ml×3). Vacuum rotary steaming at 20deg.C to obtain crude product, dissolving the crude product with 40ml DCM, dripping into 400ml methyl tert-butyl ether under rapid stirring, and filtering to obtain the first-batch solid product Fmoc-NH-PEG 8 -CO-Val-Ala-PABC and mother liquor. The mother liquor is distilled in vacuum at 20 ℃ to obtain crude product, the crude product is dissolved by 10ml of DCM, dropped into 100ml of methyl tertiary butyl ether under rapid stirring and filtered to obtain a second batch of solid product Fmoc-NH-PEG 8 -CO-Val-Ala-PABC, combining the two batches to give 14.3g yellow colloidal product (Fmoc-NH-PEG 8 -CO-Val-Ala-PABC), yield 78%.
Example 7
Fmoc-NH-PEG 8 CO-Val-Ala-PABC (552.3 mg,0.5 mmol) was dissolved in 3ml DMF in the reaction tube, after 10 minutes of ice bath (about 5 ℃ C.),DOX (doxorubicin 274.2mg,0.5112 mmol) was added,
DIPEA (196ul, 1.2822 mmol) was then added and reacted overnight under ice bath. The reaction solution was poured into methyl tert-butyl ether under stirring, water 1:1 (30 ml), to give a red gummy solid. The red gummy solid was dissolved in DMF2ml and methyl tert-butyl ether was recrystallized from water 1:1 (20 ml) to give crude 1. Crude 1 was dissolved in DCM 2ml and poured into methyl tert-butyl ether (20 ml) under stirring to crystallize to give a dispersed dark red solid which was suction filtered, washed with methyl tert-butyl ether (5 ml. Times.3), distilled off under vacuum at room temperature and dried with oil pump to give 505mg of dark red solid (Fmoc-NH-PEG) 8 -CO-Val-Ala-PABC-DOX) in 67% yield.
Example 8
Fmoc-NH-PEG 8 -CO-Val-Ala-PABC-DOX (1 g,0.663 mmol) was dissolved in 10ml DMF, DBU (1, 8-diazabicyclo undec-7-ene) (264 mg,2.39 mmol) was dissolved in a small amount of solvent and added to the reaction solution for 45 seconds. The reaction solution was poured into methyl tert-butyl ether (100 ml) to which lactic acid (480 mg) was added under stirring to give crude 1 as a red gum. The crude 1 was dissolved in 10ml of methanol and poured into methyl tert-butyl ether (100 ml) under stirring for crystallization to give crude 2 as a red solid. Crude 2 was dissolved with DCM: meoh=4:1 (10 ml) and added to 100ml of methyl tert-butyl ether for crystallization to give 900mg of red powdery solid (NH 2 -PEG 8 -CO-Val-Ala-PABC-DOX) in 98% yield.
Example 9
Weighing a compound shown in a formula 13 (the preparation method can refer to CN 201910524576.0), completely dissolving the compound in a mixed solution of DMF and DMSO, adding the compound shown in the formula 9, stirring uniformly, adding DIEA, reacting at room temperature for 24 hours, directly dialyzing the solution by using a DMSO-water gradient, detecting the doxorubicin and the derivative thereof by using HPLC, and freeze-drying after the dialysis is finished to obtain the pectin-doxorubicin conjugate.
Confirmation of pectin-doxorubicin conjugate:
1 H NMR(400MHz，DMSO-d 6 )δppm:14.04(s，1H)，13.27(s，1H)，9.88-9.90(s，1H)，8.33-6.81(m,10H)，5.47-3.39(m)，1.95-0.85(m).
the pectin-doxorubicin conjugate has the following structure:
comparative examples
The compound represented by formula 9 was synthesized according to the method described in CN 201910524576.0:
the specific yields are shown below:
| numbering of compounds | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | Total yield of |
| Yield is good | 95％ | 94％ | 53％ | 25％ | 78％ | 66％ | 35％ | 90％ | 1.9％ |
The foregoing embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the protection scope of the present invention and the optimization of the synthetic route. All equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be included within the scope of the present invention.
Claims (5)
1. A method of preparing a pectin-doxorubicin conjugate intermediate, wherein the pectin-doxorubicin conjugate intermediate has a structure according to formula (I):
b-c-d-e（I）
in the formula (I), the main structure of b is PEG n C is an enzymatic cleavage group, polypeptide or polypeptide derivative, d is a self-degrading group, e is doxorubicin DOX;
the method comprises the following specific steps:
1) From Val-Ala-PABOH and Fmoc-NH-PEG 8 Fmoc-NH-PEG obtained by the reaction of-COOH 8 CO-Val-Ala-PABOH, fmoc-NH-PEG 8 -CO-Val-Ala-PABOH passageFmoc-NH-PEG 8 Fmoc-NH-PEG preparation by-CO-Val-Ala-PABC-PNPO 8 -CO-Val-Ala-PABC-DOX, PNPO representing p-nitrophenoxy;
2) Fmoc-NH-PEG in the presence of DBU 8 Fmoc-deprotection of the protecting group-CO-Val-Ala-PABC-DOX to give NH 2 -PEG 8 -CO-Val-Ala-PABC-DOX。
2. The method of claim 1, wherein the Fmoc-NH-PEG is used as the catalyst 8 The reaction of-CO-Val-Ala-PABOH with DPNP in the presence of DIEA to produce Fmoc-NH-PEG 8 -CO-Ala-PABC-PNPO, DPNP is di (p-nitrophenyl) carbonate.
3. The method of claim 1, wherein Fmoc is deprotected from Fmoc-Val-Ala-PABOH in the presence of a non-nucleophilic or weakly nucleophilic basic reagent; the alkaline reagent is selected from piperidine, fatty amine and alkaloid.
4. The process according to claim 3, wherein Val-Ala-PABOH is obtained by removing the Fmoc protecting group in the presence of DEA.
5. The preparation method according to any one of claims 1 to 4, characterized by the specific steps of:
；
the Fmoc-NH-PEG 8 the-COOH structure is shown below:
。
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