Search

CN-121974965-A - Synthesis method and application of beta-adamantane galactose thioglycoside and galactosamine derivative thereof

CN121974965ACN 121974965 ACN121974965 ACN 121974965ACN-121974965-A

Abstract

The invention discloses a synthesis method and application of beta-adamantane galactose thioglycoside and galactosamine derivatives thereof, the method comprises the steps of feeding at 0-5 ℃, dissolving a compound 1 and adamantane in anhydrous dichloromethane, adding titanium tetrachloride and cobalt dichloride for synergistic catalysis, heating to 20-30 ℃ for reaction for 10-14 h, quenching, extracting, drying, concentrating under reduced pressure and purifying by column chromatography to obtain a compound 2. The method has the advantages of easily obtained raw materials, convenient operation, small peculiar smell, mild and easily controlled reaction conditions, high synthesis yield and capability of realizing industrialized amplification, and the established glycosylation application system is suitable for 8 types of different glycosyl acceptors, has stable product yield and strong process universality, can be widely applied to synthesis of disaccharides and oligosaccharides, glycosylation modification and synthesis of complex galactose (amine) -containing drug molecules such as anti-infection, anti-tumor and antiviral drugs, has remarkable industrialized application value and wide market prospect in the fields of glycochemistry, drug synthesis and biological medicine, and completely meets the industrial production requirements.

Inventors

  • GUO XING
  • LI DONGWEI
  • MAO WEIXIAN
  • LIU YUELING
  • SUN BAOLONG
  • REN WENWU
  • ZHOU QIANG
  • YU LINGBO
  • ZHANG MINGLIANG

Assignees

  • 天津药明康德新药开发有限公司

Dates

Publication Date
20260505
Application Date
20260311

Claims (10)

  1. 1. The synthesis method of the beta-adamantane galactose thioglycoside and the galactosamine derivative thereof is characterized by comprising the steps of feeding at 0-5 ℃, dissolving a compound 1 and adamantane in anhydrous dichloromethane, adding titanium tetrachloride and cobalt dichloride for synergistic catalysis, heating to 20-30 ℃ for reaction for 10-14 hours, quenching, extracting, drying, concentrating under reduced pressure and purifying by column chromatography to obtain a compound 2; The structural formula of the compound 1 is as follows: ; The structural formula of the compound 2 is as follows: ; Wherein R 1 is OAc or NHAc.
  2. 2. The method for synthesizing β -adamantane galactosylthio glycoside and galactosamine derivatives thereof according to claim 1, wherein the molar ratio of said compound 1 to adamantane thiol is 1 (2.0-3.0).
  3. 3. The method for synthesizing β -adamantane galactosylglycoside and galactosamine derivatives thereof according to claim 2, wherein the molar ratio of said compound 1 to adamantane thiol is 1:2.5.
  4. 4. The method for synthesizing β -adamantane galactosylthio glycoside and galactosamine derivatives thereof according to claim 1, wherein the molar ratio of titanium tetrachloride to compound 1 is 1 (0.8-1.2), and the molar ratio of cobalt dichloride to compound 1 is 1 (0.4-0.6).
  5. 5. The method for synthesizing β -adamantane galactosylglycoside and galactosamine derivatives thereof according to claim 4, wherein the molar ratio of said titanium tetrachloride to compound 1 is 1:1.0, and the molar ratio of said cobalt dichloride to compound 1 is 1:0.5.
  6. 6. The method for synthesizing beta-adamantane galactosylthio glycoside and galactosamine derivatives thereof according to claim 1, wherein the reaction condition is that the feeding temperature is 0 ℃, and the temperature is raised to 25 ℃ for reaction for 12 hours.
  7. 7. Use of β -adamantane galactosylthioglycoside and galactosamine derivatives thereof in chemical glycosylation, said β -adamantane galactosylthioglycoside and galactosamine derivatives thereof being synthesized by the synthesis method according to any one of claims 1-6, characterized in that it comprises the steps of: S1, dissolving a compound 2 in a mixed solvent of anhydrous dichloromethane and anhydrous acetonitrile, adding a glycosyl acceptor compound R 2 OH and a 4A molecular sieve, and reacting for 0.5-1.5 hours at 20-30 ℃; S2, cooling the reaction system to-80 to-75 ℃, adding N-iodosuccinimide and trifluoromethanesulfonic acid, reacting for 10-14 hours at the constant temperature of-80 to-75 ℃, quenching, extracting, drying, concentrating under reduced pressure and purifying by column chromatography after the reaction is finished to obtain a compound 3; The structural formula of the compound 3 is as follows: ; Wherein the glycosyl acceptor compound R 2 OH is a hydroxyl-containing organic compound, and R 2 comprises an alkyl group, an aromatic ring, a sugar ring, a heteroatom chain, a carboxylic acid ester and an amino alcohol.
  8. 8. The use of β -adamantane galactose thioglycoside and its galactosamine derivatives for chemical glycosylation according to claim 7, characterized in that said compound 2 and glycosyl acceptor compound R 2 OH molar ratio is 1 (2.5-3.5), said anhydrous dichloromethane and anhydrous acetonitrile volume ratio is (1.5-2.5): 1, said 4A molecular sieve mass is 1.5-2.5 times of compound 2 mass, said N-iodosuccinimide molar ratio to compound 2 is (2.0-2.5): 1, and said trifluoromethanesulfonic acid molar ratio to compound 2 is (0.4-0.6): 1.
  9. 9. The use of β -adamantane galactosylglycoside and galactosamine derivatives thereof in chemical glycosylation according to claim 8, characterized in that the molar ratio of compound 2 to glycosyl acceptor compound R 2 OH is 1:3.0, the volume ratio of anhydrous dichloromethane to anhydrous acetonitrile is 2.0:1, the mass of 4A molecular sieve is 2.0 times the mass of compound 2, the molar ratio of N-iodosuccinimide to compound 2 is 2.4:1, and the molar ratio of trifluoromethanesulfonic acid to compound 2 is 0.5:1.
  10. 10. The use of β -adamantane galactosylthio glycoside and galactosamine derivatives thereof in chemical glycosylation according to claim 1, characterized in that said glycosyl acceptor compound R 2 OH is p-methylphenol, p-methoxyphenol, N-octanol, azido-tri-polyethylene glycol, benzyl 2,4, 6-tri-O-acetyl- β -D-glucopyranoside, 2- (1-styryl) benzoic acid, benzyl 5-hydroxypentanoate and benzyl N- (6-hydroxyhexyl) carbamate.

Description

Synthesis method and application of beta-adamantane galactose thioglycoside and galactosamine derivative thereof Technical Field The invention relates to the technical field of biopharmaceutical synthesis, in particular to a synthesis method and application of beta-adamantane galactose thioglycoside and galactosamine derivatives thereof. Background The chemical glycosyl modification is one of the key technical means in the field of drug research and development, and by carrying out glycosylation modification on drug molecules, the pharmacological activity, targeting property, water solubility and bioavailability of the drug can be obviously improved, and simultaneously toxic and side effects are reduced, so that the chemical glycosyl modification is widely applied to innovative drug research and development and drug structure optimization. Adamantane sulfanyl compounds, which are a novel class of chemical glycosylation donors, exhibit unique advantages in terms of stereospecific control of glycosylation reactions by virtue of the large steric hindrance of adamantane groups, have become an important donor class for disaccharide, trisaccharide and even oligosaccharide synthesis. The thioglycoside donor containing galactose and galactosamine structure is core intermediate for synthesizing medicine molecule containing galactose structure with the functions of resisting infection, tumor, virus, etc. and has irreplaceable application value. However, the synthesis method of beta-adamantane galactosamine sulfadiazine and the systematic application research thereof are relatively deficient at present. The existing thioglycoside donors are mostly synthesized by adopting sulfur source reagents such as ethanethiol, thiophenol and the like, the reagents have strong peculiar smell and higher toxicity, high-grade protection measures are needed in the production process, the operation difficulty is high, the industrial amplification is not facilitated, meanwhile, the stereospecificity and the precision control of beta-type products are difficult to realize by the traditional synthesis method, the stereoselectivity of glycosylation reaction is poor, the purity of the products is low, and the subsequent separation and purification cost is high. In addition, the prior art lacks a large-scale glycosylation application scheme taking beta-adamantane galactose thioglycoside and beta-adamantane galactose amine thioglycoside as donors, and has not realized high-efficiency and stereospecific glycosylation reaction of the donors and various types of glycosyl acceptors, and can not meet the synthesis requirement of complex galactose (amine) -containing drug molecules. Therefore, the method for synthesizing the beta-adamantane galactose thioglycoside and the beta-adamantane galactose amine thioglycoside is developed, which has the advantages of easily available raw materials, convenient operation, small peculiar smell, high yield and suitability for industrial production, and meanwhile, a high-efficiency stereospecific glycosylation application system of the compound is established, the technical problems of poor suitability of the synthesis process, low stereoselectivity of the glycosylation reaction and the like in the prior art are solved, and the method becomes an urgent requirement in the fields of sugar chemistry and medicine synthesis. Disclosure of Invention In order to solve the technical problems, the invention provides a synthesis method of beta-adamantane galactose thioglycoside and galactosamine derivatives thereof, which comprises the steps of feeding at 0-5 ℃, dissolving a compound 1 and adamantane in anhydrous dichloromethane, adding titanium tetrachloride and cobalt dichloride for synergistic catalysis, heating to 20-30 ℃ for reaction for 10-14 h, quenching, extracting, drying, concentrating under reduced pressure and purifying by column chromatography to obtain a compound 2; The structural formula of the compound 1 is as follows: ; The structural formula of the compound 2 is as follows: ; Wherein R 1 is OAc or NHAc. Preferably, the reaction conditions are such that the feed temperature is 0 ℃, and the reaction is carried out for 12 hours at a temperature of 25 ℃. Specifically, the molar ratio of the compound 1 to the adamantanethiol is 1 (2.0-3.0). Preferably, the molar ratio of compound 1 to adamantanethiol is 1:2.5. Specifically, the molar ratio of the titanium tetrachloride to the compound 1 is 1 (0.8-1.2), and the molar ratio of the cobalt dichloride to the compound 1 is 1 (0.4-0.6). Preferably, the molar ratio of titanium tetrachloride to compound 1 is 1:1.0 and the molar ratio of cobalt dichloride to compound 1 is 1:0.5. In a second aspect, the present application also provides an application of β -adamantane galactosylthio-glycoside and galactosamine derivatives thereof in chemical glycosylation, said β -adamantane galactosylthio-glycoside and galactosamine derivatives thereof being synthesized by the aforement