- Preparation method of miglitol
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The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of miglitol. The method comprises the following steps: (1) adding Pd/C and SM-1 into a reaction solvent in a high-pressure reaction kettle, adding an acid, conducting stirring, controlling the temperature and pressure, carrying out hydrogenation reaction, cooling the reaction solution to room temperature after the reaction is finished, conducting filtering, and carrying out reduced pressure concentration until the reaction solution is dry to obtain a solid; and (2) adding an organic solvent into the obtained solid for dissolution, adding a crystallization solvent for crystallization, completely conducting crystallizing, conducting filtering, and carrying out vacuum drying toobtain a target compound miglitol. Compared with the prior art, the invention provides a simple, convenient and efficient method for preparing miglitol, and the whole synthesis method has the advantages of short route, simple operation steps, high reaction yield, high product purity, mild reaction conditions, effective shortening of the production period, and suitableness for industrial scale-upproduction.
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Paragraph 0031-0060
(2021/01/11)
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- Iminosugars: Effects of stereochemistry, ring size, and n-substituents on glucosidase activities
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N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an SN2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-glucosidase with IC50 41 μM and 138 μM, respectively, using DNJ as reference (IC50 134 μM). On the other hand, β-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 μM, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC50 172 μM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 μM) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides α-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest β-glucosidase inhibitors of the series with IC50 of 4 μM.
- Zamoner, Luís O. B.,Arag?o-Leoneti, Valquiria,Carvalho, Ivone
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- Preparation method for miglitol
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The invention discloses a preparation method for miglitol. The method comprises the following steps: selecting 6-deoxy-6-hydroxyethylamino-alpha-L-sorbose as a raw material, adding an alcohol solvent,performing a catalytic hydrogenation reaction under a certain pressure condition in the presence of a hydrogen gas, then performing pressure filtration, performing concentration, performing crystallization, performing vacuum filtration, performing washing, and performing vacuum drying to obtain the miglitol crystal. According to the invention, the reaction time is 7-8h, the temperature is 20-30 DEG C, the yield is greater than 90%, and the purity is greater than 99% (HPLC detection); and the reagents used by the method are green, environmentally friendly, pollution-free, economical and practical, the reaction yield is high, and the method is simple and convenient for operation, and suitable for industrialized mass production.
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Paragraph 0016; 0018; 0019
(2018/04/03)
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- One pot oxidative dehydration - oxidation of polyhydroxyhexanal oxime to polyhydroxy oxohexanenitrile: A versatile methodology for the facile access of azasugar alkaloids
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A unique oxidative dehydration-oxidation of polyhydroxy-oxime (7) to the corresponding ketonitrile (8) in one pot is reported for the first time in carbohydrate literature. Key ketonitrile intermediate (8) upon palladium hydroxide mediated cascade reaction afforded 1-deoxynojirimycin (DNJ) 1b in moderate diastereoselectivity. The cascade reaction involves the conversion of nitrile to amine, heteroannulation, reduction of the imine and subsequent debenzylation to furnish the azasugars. This oxidative dehydration-oxidation and reductive heteroannulation methodology is successfully utilized for the total synthesis of 1-deoxynojirimycin (1b), miglitol (2) and miglustat (3).
- Khobare, Sandip R.,Gajare, Vikas,Reddy, E. Vishnuvardhan,Datrika, Rajender,Banda, Malavika,Siddaiah, Vidavalur,Pachore, Sharad S.,Timanna, Upadhya,Dahanukar, Vilas H.,Syam Kumar
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- Facile and stereo-controlled synthesis of 2-deoxynojirimycin, Miglustat and Miglitol
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A novel and facile synthesis of a series of the biologically significant iminosugar derivatives including 2-deoxynojirimycin, Miglustat and Miglitol is reported. The synthesis features a strategic double inversion mechanism for securing the desired stereochemistry at C5 position of such glucose-type carbohydrate mimetics, representing a practical and remarkable improvement on the previously reported method that suffers from the loss of the stereo-control during the reaction process. Crown Copyright
- Zhang, Zhen-Xing,Wu, Baolin,Wang, Bin,Li, Tie-Hai,Zhang, Peng-Fei,Guo, Li-Na,Wang, Wen-Jun,Zhao, Wei,Wang, Peng George
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p. 3802 - 3804
(2011/08/09)
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- Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation
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The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1- deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the L-ido derivative of 2, L-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.
- Wennekes, Tom,Meijer, Alfred J.,Groen, Albert K.,Boot, Rolf G.,Groener, Johanna E.,Van Eijk, Marco,Ottenhoff, Roelof,Bijl, Nora,Ghauharali, Karen,Song, Hang,O'Shea, Tom J.,Liu, Hanlan,Yew, Nelson,Copeland, Diane,Van Den Berg, Richard J.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Aerts, Johannes M.
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supporting information; experimental part
p. 689 - 698
(2010/07/06)
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- D-fructose-6-phosphate aldolase in organic synthesis: Cascade chemical-enzymatic preparation of sugar-relafed polyhydroxylated compounds
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Novel aldol addition reactions of dihydroxyacetone (DHA) and hydroxyacetone (HA) to a variety of aldehydes catalyzed by D-fructose-6-phosphate aldolase (FSA) are presented. In a chemical-enzymatic cascade reaction approach, 1-deoxynojirimycin and 1-deoxymannojirimycin were synthesized starting from (R)- and (S)-3-(N-Cbz-amino)-2-hydroxypropanal, respectively. Furthermore, 1,4-dideoxy1,4-imino-D-arabinitol and 1,4,5-trideoxy-1,4-imino-D-arabinitol were prepared from N-Cbz-glycinal, 1 -Deoxy-D-xylulose was also synthesized by using HA as the donor and either 2-benzyloxyethanal or 2-hydroxyethanal as acceptors. In both cases the enzymatic aldol addition reaction was fully stereoselective, but with 2-hydroxyethanal 17% of the epimeric product at C2, 1-deoxy-D-erythro-2-pentulose, was observed due to enolization/epimerization during the isolation steps. It was also observed that D-(-)-threose is a good acceptor substrate for FSA, opening new synthetic possibilities for the preparation of important novel complex carbohydrate-related compounds from aldoses. To illustrate this, 1-deoxy-D-ido-hept-2-ulose was obtained stereoselectively by the addition of HA to D-(-)-threose, catalyzed by FSA. It was found that the reaction performance depended strongly on the donor substrate, HA being the one that gave the best conversions to the aldol adduct. The examples presented in this work show the valuable synthetic potential of FSA for the construction of chiral complex polyhydroxylated sugar-type structures.
- Concia, Alda Lisa,Lozano, Caries,Castillo, Jose A.,Parella, Teodor,Joglar, Jesus,Clapes, Pere
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experimental part
p. 3808 - 3816
(2010/01/16)
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- USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
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The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
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- New sugar-mimic alkaloids from the pods of Angylocalyx pynaertii
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Chromatographic separation of the pod extract of Angylocalyx pynaertii resulted in the isolation of 13 sugar-mimic alkaloids (1-13). The structures of the new alkaloids were elucidated by spectroscopic methods as the 6-O-β-D-glucoside (10) and N-hydroxyethyl derivative (11) of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) (1), 1,6-dideoxynojirimycin (12), and 1,3,4-trideoxynojirimycin (13). 2,5-Imino-1,2,5-trideoxy-L-glucitol (7), 2,5-dideoxy-2,5-imino-D-fucitol (8), and β-homofuconojifimycin (9), isolated from the pods as well as the bark, were very specific inhibitors of α-L-fucosidase with no significant inhibitory activity toward other glycosidases. In this work, 1,4-dideoxy-1,4-imino-D-ribitol (6) was found to be a better inhibitor of lysosomal β-mannosidase than 2,5-imino-1,2,5-trideoxy-D-mannitol (2). N-Hydroxyethyl-1-deoxynojirimycin (miglitol), which is commercially available for the treatment of diabetes, retained its inhibitory potential toward rat intestinal maltase and sucrase, whereas 11 and the synthetic N-hydroxyethyl derivative of 2,5-dideoxy-2,5-imino-D-mannitol markedly lowered or abolished their inhibition toward all enzymes tested.
- Yasuda, Kayo,Kizu, Haruhisa,Yamashita, Toru,Kameda, Yukihiko,Kato, Atsushi,Nash, Robert J.,Fleet, George W. J.,Molyneux, Russell J.,Asano, Naoki
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p. 198 - 202
(2007/10/03)
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- Lipophilic prodrugs of 1-deoxynojirimycin derivatives
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We report a new synthesis of Miglitol, and its conversion to a lipophilic prodrug. The same procedure permits the preparation of a prodrug of 1-desoxynojirimycin and probably of other 1-deoxynojirimycin derivatives. (C) 2000 Elsevier Science Ltd.
- Fouace,Therisod
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p. 7313 - 7315
(2007/10/03)
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- Process for preparing 1-deoxynojirimycin and N-derivatives thereof
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A process for preparing a 1-deoxynojirimycin of the formula STR1 in which R is hydrogen, optionally substituted alkyl or aralkyl, which comprises converting D-glucose to an aminosorbitol STR2 protecting the amino group of the aminosorbitol with an alkalinically detachable group to form the protected compound of the formula STR3 in which X is an alkalinically detachable protective group, microbiologically oxidizing the protected compound to an oxidation product of the formula STR4 alkalinically splitting off the protective group X to form an aminosorbose of the formula STR5 and reducing the aminosorbose.
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