background and overview[1]
edci (dimethyldiiminoadipate dihydrochloride) is a water-soluble carbodiimide. it is used as an activating reagent for carboxyl groups in amide synthesis and is also used to activate phosphate ester groups. , cross-linking of proteins and nucleic acids and preparation of immunoconjugates. the ph range when used is 4.0-6.0, and it is often used in combination with n-hydroxysuccinimide (nhs) or n-hydroxysulfosuccinimide to improve coupling efficiency. in organic chemistry, dimethyl diiminoadipate dihydrochloride and the catalyst 4-dimethylaminopyridine (dmap) are used to esterify carboxylic acids and alcohols.
structure
apply[1-4]
edci (dimethyldiiminoadipic acid dihydrochloride) application examples are as follows:
1) for the preparation of doxorubicin prodrugs, potassium permanganate and polyethylene glycol are oxidized to generate polyethylene glycol diacid; through edci (dimethyl diimide adipate dihydrochloride), polyethylene glycol diacid reacts with tert-butylcarbazate and removes the boc protecting group to form a polyethylene glycol dihydrazide intermediate product; through edci (diiminohexane dihydrazide) through the catalytic action of acid dimethyl ester dihydrochloride), the intermediate product is introduced into the 13-position carbonyl group of doxorubicin to obtain the target compound doxorubicin-polyethylene glycol diacid hydrazone linker. this prodrug may enhance the anti-tumor effect of doxorubicin, reduce drug side effects, improve targeting, and provide new ideas for the development of anti-tumor drugs.
2) for the synthesis of mmaf intermediate pentapeptide, including the following steps: (1) using 1eq of val-dil-dap-phe-ome and 3.0eq of boc-n-me-val as raw materials, add two dissolve methyl chloride; (2) at 0°c, add 3.0eq of n,n-diisopropylethylamine and 1.1eq of edci (dimethyldiiminoadipate dihydrochloride) (1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and 1.1eq of hobt (1-hydroxybenzotriazole), stir at 25°c for 18h; (3) add water to dilute the reaction the system was extracted three times with ethyl acetate, the organic phase was washed with saturated nacl, dried over anhydrous na2so4, filtered, and the crude product was obtained after removing the solvent; (4) mmaf intermediate pentapeptide was obtained through column purification. the invention is reasonably designed. it uses edci (dimethyl diimide adipate dihydrochloride) and hobt as condensation agents. its synthesis process is simple, the product is easy to purify, the product purity is as high as 95% or more, and the product yield is as high as 84%, while reducing production costs.
3) used for the preparation of vildagliptin, including using l-prolinamide as raw material, dehydration reaction with cyanuric chloride to generate (s)-2-cyanopyrrolidine; (s)-2 – cyanopyrrolidine reacts with hydrogen chloride to form a salt to obtain intermediate-1; intermediate-1 is reacted with chloroacetic acid in edci (dimethyldiiminoadipate dihydrochloride) as the condensing agent, hobt as the catalyst, and diea intermediate-2 is obtained by reacting under the conditions of acid binding agent; intermediate-2 reacts with 3-amino-1-adamantanol to obtain vildagliptin, which is filtered, concentrated, crystallized, and filtered again to obtain vildagliptin. the crude product is refined with acetone to obtain vildagliptin finished product. the present invention creates a new route, which can reduce the generation of by-products in each step, and combines the vildagliptin disubstituted by-products and 3-amino-1 in the product. -the content of adamantanol is reduced to less than 0.1%, which effectively improves the yield and purity of vildagliptin. the raw materials are easily available and the conditions are mild, making it suitable for industrial large-scale production.
4) for the preparation of baicalin to be loaded, mpeg5k-nh2 and blg-nca were first dissolved in anhydrous dmf, and reprecipitated with glacial ether three times to obtain mpeg-pblg, and then the naoh solution was hydrolyzed to mpeg-pblg. in pblg, and remove the protecting group, and then acidify with hcl solution to obtain mpeg-pga. finally, dissolve mpeg-pga in anhydrous dmf, and add edci (dimethyl diimide adipate dihydrochloride). ) to react, and then add m-aminophenylboronic acid to react to obtain a product, and then dialyze and freeze-dry the product to obtain pseudo-loaded baicalin. this preparation method is simple to operate and has strong stability, and the prepared pseudo-loaded baicalin is used for treatment ulcerative colitis.
main reference materials
[1] cn200910023552.3 preparation method and application of doxorubicin prodrug
[2] cn201310666.6 a synthesis method of mmaf intermediate pentapeptide
[3] cn201710202219.3 a preparation method of vildagliptin
[4] cn201910190198.7 a preparation method of intended to load baicalin