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【结 构 式】

【药物名称】SanOrg-123781, SR-123781A

【化学名称】Methyl O-2,3,4,6-tetra-O-sulfo-alpha-D-glucopyranosyl-(1--4)-O-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl-(1--4)-O-2,3,6-tri-O-sulfo-beta-D-glucopyranosyl-(1--4)-O-2,3-di-O-methyl-6-O-sulfo-alpha-D-glucoyranosyl-(1--4)-[O-2,3,6-tri-O-methyl-beta-D-glucopyranosyl-(1--4)-O-2,3,6-tri-O-methyl-alpha-D-glucopyranosyl-(1--4)]3-O-2,3,6-tri-O-methyl-beta-D-glucopyranosyl-(1--4)-O-2,3-di-O-methyl-6-O-sulfo-alpha-D-glucopyranosyl-(1--4)-O-2,3-di-O-methyl-beta-D-glucopyranurosyl-(1--4)-O-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl-(1--4)-O-2,3-di-O-methyl-alpha-L-idopyranurosyl]-(1--4)-3-O-methyl-alpha-D-glucopyranoside bis(hydrogen sulfate) nonadecasodium salt

【CA登记号】232602-93-6

【 分 子 式 】C127H201Na19O134S17

【 分 子 量 】4853.83182

【开发单位】Sanofi-synthélabo (Originator), Organon (Codevelopment)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors, Thrombin Inhibitors

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11

合成路线1

The intermediate thioglycoside (V) is prepared as follows. Esterification of maltotriose (I) with acetic anhydride and sodium acetate provides peracetate (II). Subsequent reaction of (II) with ethanethiol in the presence of boron trifluoride etherate yields the ethyl thiopyranoside (III). Removal of the acetate esters of (III) is effected by methanolysis in the presence of potassium tert-butoxide, yielding (IV). Then, reesterification of (IV) by means of benzoyl chloride and pyridine furnishes the target intermediate (V).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 58132 (3R,4R,5S,6R)-5-[((2S,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}tetrahydro-2H-pyran-2-yl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4-triol; D-(+)-Maltotriose; D-Maltotriose; Maltotriose; O-alpha-D-Glucopyranosyl-(1->4)-O-alpha-D-glucopyranosyl-(1->4 )-D-glucose 1109-28-0 C18H32O16 详情 详情
(II) 58133 (2R,3R,4S,5R,6R)-3-(acetyloxy)-6-[(acetyloxy)methyl]-5-({(2R,3R,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-2-({(2R,3R,4S,5R,6S)-4,5,6-tris(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-2H-pyran-3-yl}oxy)tetrahydro-2H-pyran-4-yl acetate C40H54O27 详情 详情
(III) 58134 (2R,3R,4S,5R,6R)-3-(acetyloxy)-6-[(acetyloxy)methyl]-2-{[(2R,3S,4S,5R,6S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]-6-(ethylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy}-5-({(2R,3R,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)tetrahydro-2H-pyran-4-yl acetate C40H56O25S 详情 详情
(IV) 58135 (2R,3R,4S,5S,6R)-2-{[(2R,3S,4R,5R,6R)-6-{[(2R,3S,4R,5R,6S)-6-(ethylsulfanyl)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol C20H36O15S 详情 详情
(V) 58136 (2S,3R,4S,5S,6R)-3-(benzoyloxy)-6-[(benzoyloxy)methyl]-5-{[(2R,3R,4S,5R,6R)-3,4-bis(benzoyloxy)-6-[(benzoyloxy)methyl]-5-({(2R,3R,4S,5R,6R)-3,4,5-tris(benzoyloxy)-6-[(benzoyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)tetrahydro-2H-pyran-2-yl]oxy}-2-(ethylsulfanyl)tetrahydro-2H-pyran-4-yl benzoate C90H76O25S 详情 详情

合成路线2

The known disaccharide thioglucoside (VI) is esterified by means of benzoyl chloride and pyridine to give the penta-benzoate (VII). Coupling between thioglycoside (VII) and 2,3-di-O-methyl-1,6-anhydro-D-glucose (VIII) is effected by treatment with N-iodosuccinimide and trifluoromethanesulfonic acid, yielding trisaccharide (IX). After methanolysis of the benzoate esters, the resultant penta-hydroxy compound (X) is alkylated with iodomethane and NaH, leading to the corresponding methyl ether (XI). Hydrolysis of the benzylidene acetal of (XI) with 80% AcOH provides diol (XII). The primary hydroxyl group of (XII) is then selectively esterified by using 1-(benzoyloxy)-benzotriazole to produce the mono-benzoate (XIII).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 58137 (2R,4aR,6R,7R,8R,8aS)-6-{[(2R,3S,4R,5R,6S)-6-(ethylsulfanyl)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol C21H30O10S 详情 详情
(VII) 58138 (2R,4aR,6R,7R,8S,8aR)-7-(benzoyloxy)-6-{[(2R,3S,4S,5R,6S)-4,5-bis(benzoyloxy)-2-[(benzoyloxy)methyl]-6-(ethylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl benzoate C56H50O15S 详情 详情
(VIII) 58139 (1R,2S,3S,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]octan-2-ol C8H14O5 详情 详情
(IX) 58140 (2R,4aR,6R,7R,8S,8aR)-7-(benzoyloxy)-6-[((2R,3R,4S,5R,6R)-4,5-bis(benzoyloxy)-2-[(benzoyloxy)methyl]-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}tetrahydro-2H-pyran-3-yl)oxy]-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl C62H58O20 详情 详情
(X) 58141 (2R,4aR,6R,7R,8R,8aS)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol C27H38O15 详情 详情
(XI) 58142 (2R,4aR,6R,7R,8R,8aS)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl methyl ether; (2R,4aR,6R,7R,8R,8aS)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-7,8-dimethoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine C32H48O15 详情 详情
(XII) 58143 (2R,3S,4S,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-2-(hydroxymethyl)-4,5-dimethoxytetrahydro-2H-pyran-3-ol C25H44O15 详情 详情
(XIII) 58144 ((2R,3S,4S,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-yl)methyl benzoate C32H48O16 详情 详情

合成路线3

Coupling between trisaccharide (XIII) and thioglycoside (VII) using N-iodosuccinimide/trifluoromethanesulfonic acid furnishes pentasaccharide (XIV). After methanolysis of the benzoate esters of (XIV), the poly-methyl ether (XV) is prepared by methylation of (XIV) with iodomethane and NaH. Acidic hydrolysis of the benzylidene acetal (XV), followed by selective esterification with 1-(benzoyloxy)-benzotriazole affords benzoate (XVI).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 58138 (2R,4aR,6R,7R,8S,8aR)-7-(benzoyloxy)-6-{[(2R,3S,4S,5R,6S)-4,5-bis(benzoyloxy)-2-[(benzoyloxy)methyl]-6-(ethylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl benzoate C56H50O15S 详情 详情
(VIII) 58144 ((2R,3S,4S,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-yl)methyl benzoate C32H48O16 详情 详情
(IX) 58145 ((2R,3S,4R,5R,6R)-3-({(2S,3R,4S,5R,6R)-5-{[(2R,4aR,6R,7R,8S,8aR)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-3,4-bis(benzoyloxy)-6-[(benzoyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxytetrahydro-2H-pyran-2-yl)methyl benzoate C86H92O31 详情 详情
(X) 58146 (2R,4aR,6R,7R,8R,8aS)-6-{[(2R,3S,4R,5R,6S)-6-{[(2R,3S,4R,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-7,8-dimethoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine; (2R,4aR,6R,7R,8R,8aS)-6-{[(2R,3S,4R,5R,6S)-6-{[(2R,3S,4R,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-8-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl methyl ether C50H80O25 详情 详情
(XI) 58147 ((2R,3S,4S,5R,6R)-6-{[(2R,3S,4R,5R,6S)-6-{[(2R,3S,4R,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-yl)methyl benzoate C50H80O26 详情 详情

合成路线4

A new coupling of pentasaccharide (XVI) with thioglycoside (VII) produces heptasaccharide (XVII). Hydrolysis of the benzoate esters of (XVII), followed by O-methylation, yields methyl ether (XVIII).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 58138 (2R,4aR,6R,7R,8S,8aR)-7-(benzoyloxy)-6-{[(2R,3S,4S,5R,6S)-4,5-bis(benzoyloxy)-2-[(benzoyloxy)methyl]-6-(ethylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl benzoate C56H50O15S 详情 详情
(XVI) 58147 ((2R,3S,4S,5R,6R)-6-{[(2R,3S,4R,5R,6S)-6-{[(2R,3S,4R,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(1R,2S,3R,4R,5R)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-yl)methyl benzoate C50H80O26 详情 详情
(XVII) 58148 　 C104H124O41 详情 详情
(XVIII) 58149 　 C68H112O35 详情 详情

合成路线5

After acidic hydrolysis of the benzylidene acetal of (XVIII), esterification with 1-(benzoyloxy)-benzotriazole leads to (XIX). This is then coupled with a third moiety of disaccharide thioglycoside (VII), producing (XX).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 58149 　 C68H112O35 详情 详情
(XIX) 58150 　 C69H114O35 详情 详情
(XX) 58138 (2R,4aR,6R,7R,8S,8aR)-7-(benzoyloxy)-6-{[(2R,3S,4S,5R,6S)-4,5-bis(benzoyloxy)-2-[(benzoyloxy)methyl]-6-(ethylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl benzoate C56H50O15S 详情 详情
(XXI) 58151 　 C122H156O51 详情 详情

合成路线6

The nonasaccharide (XX) is transformed into (XXI) by the sequence of benzoate esters hydrolysis, O-methylation, acetal hydrolysis, and selective mono-benzoylation, following the same methods as above. The free hydroxyl group of (XXI) is subsequently protected by esterification with levulinic acid (XXII) to give levulinate ester (XXIII). Opening of the 1,6-anhydroglucose unit of (XXIII) is then accomplished by treatment with acetic anhydride in the presence of acetic acid and trifluoroacetic acid, producing (XXIV).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 58151 　 C122H156O51 详情 详情
(XXI) 58152 　 C86H144O46 详情 详情
(XXII) 36170 4-oxopentanoic acid 123-76-2 C5H8O3 详情 详情
(XXIII) 58153 　 C91H150O48 详情 详情
(XXIV) 58154 　 C95H156O51 详情 详情

合成路线7

The glycosidic acetate group of (XXIV) is selectively hydrolyzed to (XXV) by means of morpholine in toluene. Activation of (XXV) by means of trichloroacetonitrile produces imidate (XXVI).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIV) 58154 　 C95H156O51 详情 详情
(XXV) 58155 　 C93H154O50 详情 详情
(XXVI) 58156 　 C95H154Cl3NO50 详情 详情

合成路线8

Preparation of the tetrasaccharide building block (XXXIV) is carried out as follows. The disaccharide benzoate ester (XXVII) is hydrolyzed to alcohol (XXVIII), which is subsequently alkylated with iodomethane and NaH to the methyl ether (XXIX). Acidic hydrolysis of the acetonide group of (XXIX) provides diol (XXX). The primary alcohol of (XXX) is then oxidized by means of TEMPO and NaOCl, yielding carboxylic acid (XXXI), which is further converted to the benzyl ester (XXXII) upon treatment with benzyl bromide and KHCO3. Coupling of the disaccharide acceptor (XXXII) with imidate (XXXIII) in the presence of tert-butyldimethylsilyl triflate, followed by removal of the levulinate ester with hydrazine acetate, furnishes tetrasaccharide (XXXIV).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVII) 58157 (4aS,6R,7R,8S,8aS)-6-({(2R,3S,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-8-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl benzoate C39H48O12 详情 详情
(XXVIII) 58158 (4aS,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-8-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ol C32H44O11 详情 详情
(XXIX) 58159 (4aS,6R,7R,8R,8aS)-6-({(2R,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl methyl ether; (4aS,6R,7R,8R,8aS)-6-({(2R,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-7,8-dimethoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxine C33H46O11 详情 详情
(XXX) 58160 (2S,3S,4S,5R,6S)-6-({(2R,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-2-(hydroxymethyl)-4,5-dimethoxytetrahydro-2H-pyran-3-ol C30H42O11 详情 详情
(XXXI) 58161 (2R,3S,4S,5R,6R)-6-({(2R,3S,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylic acid C30H40O12 详情 详情
(XXXII) 58162 benzyl (2R,3S,4S,5R,6R)-6-({(2R,3S,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylate C37H46O12 详情 详情
(XXXIII) 58163 benzyl (2R,3S,4R,5R,6R)-6-({(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(benzyloxy)-6-[(2,2,2-trichloroethanimidoyl)oxy]tetrahydro-2H-pyran-3-yl}oxy)-4,5-dimethoxy-3-[(4-oxopentanoyl)oxy]tetrahydro-2H-pyran-2-carboxylate C39H46Cl3NO16 详情 详情
(XXXIV) 58164 benzyl (2R,3S,4S,5R,6R)-6-{[(2R,3R,4R,5R,6S)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(benzyloxy)-6-({(2R,3S,4R,5R,6R)-6-({(2R,3S,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-2-[(benzyloxy)carbonyl]-4,5-dimethoxytetrahydro-2H-pyran-3-yl}oxy)tetrahydro-2H-pyran-3-yl]oxy}-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylate C69H84O25 详情 详情

合成路线9

The nonasaccharide imidate (XXVI) is coupled to the tetrasaccharide acceptor (XXXIV) to provide adduct (XXXV). Subsequent deprotection of the levulinate ester of (XXXV) to afford (XXXVI) is effected by treatment with hydrazine acetate.

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVI) 58156 　 C95H154Cl3NO50 详情 详情
(XXXIV) 58164 benzyl (2R,3S,4S,5R,6R)-6-{[(2R,3R,4R,5R,6S)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(benzyloxy)-6-({(2R,3S,4R,5R,6R)-6-({(2R,3S,4R,5R,6S)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2H-pyran-3-yl}oxy)-2-[(benzyloxy)carbonyl]-4,5-dimethoxytetrahydro-2H-pyran-3-yl}oxy)tetrahydro-2H-pyran-3-yl]oxy}-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylate C69H84O25 详情 详情
(XXXV) 58165 　 C162H236O74 详情 详情
(XXXVI) 58166 　 C157H230O72 详情 详情

合成路线10

Coupling of polysaccharide (XXXVI) with the thioglycoside (V) using N-iodosuccinimide and trifluromethanesulfonic acid provides (XXXVII). The benzyl ether and ester groups of (XXXVII) are then removed by hydrogenolysis in the presence of Pd/C to produce (XXXVIII).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 58136 (2S,3R,4S,5S,6R)-3-(benzoyloxy)-6-[(benzoyloxy)methyl]-5-{[(2R,3R,4S,5R,6R)-3,4-bis(benzoyloxy)-6-[(benzoyloxy)methyl]-5-({(2R,3R,4S,5R,6R)-3,4,5-tris(benzoyloxy)-6-[(benzoyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)tetrahydro-2H-pyran-2-yl]oxy}-2-(ethylsulfanyl)tetrahydro-2H-pyran-4-yl benzoate C90H76O25S 详情 详情
(XXXVI) 58166 　 C157H230O72 详情 详情
(XXXVII) 58167 　 C245H300O97 详情 详情
(XXXVIII) 58168 　 C197H263AcO95 详情 详情

合成路线11

The intermediate thioglycoside (V) is prepared as follows. Esterification of maltotriose (I) with acetic anhydride and sodium acetate provides peracetate (II). Subsequent reaction of (II) with ethanethiol in the presence of boron trifluoride etherate yields the ethyl thiopyranoside (III). Removal of the acetate esters of (III) is effected by methanolysis in the presence of potassium tert-butoxide, yielding (IV). Then, reesterification of (IV) by means of benzoyl chloride and pyridine furnishes the target intermediate (V).

参考文献 中间体
【1】 Petitou, M.; Herbert, J.-M.; Duchaussoy, P.; Basten, J.; Dreef-Tromp, C.; Driguez, P.-A.; Van Boeckel, C. (Akzo Nobel N.V.; Sanofi-Synthélabo); Synthetic polysaccharides, their method of production and pharmaceutical compsns. containing same. EP 1049721; FR 2773804; US 6528497; WO 9936443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXVIII) 58168 　 C197H263AcO95 详情 详情
(XXXIX) 58169 　 C127H220O83 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)