Idraparinux sodium, S-O-34006, Org-34006, SanOrg-34006, SR-34006, -Drug Synthesis Database

【结构式】

【药物名称】Idraparinux sodium, S-O-34006, Org-34006, SanOrg-34006, SR-34006

【化学名称】Methyl O-2,3,4-tri-O-methyl-6-O-sulfo-alpha-D-glucopyranosyl-(1--4)-O-2,3-di-O-methyl-beta-D-glucopyranuronosyl-(1--4)-O-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl-(1--4)-O-2,3-di-O-methyl-alpha-L-idopyranuronosyl-(1--4)-2,3,6-tri-O-sulfo-alpha-D-glucopyranoside nonasodium salt

【CA登记号】149920-56-9, 162610-17-5 (free acid)

【分子式】C₃₈H₅₅Na₉O₄₉S₇

【分子量】1727.18885

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

【药理作用】Anticoagulants, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, Peripheral Vascular Disease, Treatment of, Stroke, Treatment of, Coagulation Factor Xa Inhibitors

合成路线1 合成路线2

合成路线1

Glycosylation of sugar (I) with the idopyranosyl fluoride (II) by means of BF3.Et2O and molecular sieves in dichloromethane gives the disaccharide fragment (III), which is then converted into acetonide (V) by saponification of the ester functions with t-BuOK, followed by reaction with 2,2-dimethoxypropane (IV) in DMF and acidification with p-toluensulfonic acid. Methylation of acetonide (V) with MeI and NaH in DMF/MeOH provides the disaccharide (VI), which is then treated with HOAc to yield the 4',6'-diol (VII). Selective silylation of the diol (VII) with tert-butyldimethylsilyl chloride (TBDMSCl) in pyridine leads to the 6'-O-TBDMS derivative (VIII), which is condensed with levulinic acid (IX) by means of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in dioxane to give the ester (X). Compound (X) is then submitted to simultaneous Jones oxidation and TBDMS removal with CrO3 and H2SO4/H2O in acetone to provide the iduronic acid derivative (XI), which is converted into the key intermediate (XII), first by esterification with MeI and KHCO3 in DMF and then by removal of the 4'-O-levulinoyl protecting group with HOAc and hydrazine hydrate in pyridine.

参考文献中间体

【1】 del Fresno, M.; Diaz-Ricart, M.; Idraparinux Sodium. Drugs Fut 2002, 27, 7, 639.
【2】 Basten, J.E.M.; van Boeckel, C.A.A.; Westerduin, P.; et al.; Feasible synthesis and biological properties of six "non-glycosamino" glycan analogues of the antithrombin III binding heparin pentasaccharide. Bioorg Med Chem 1994, 2, 11, 1267.

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)	54143	(2R,3S,4S,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-ol	n/a	C₂₈H₃₂O₆	详情	详情
(II)	54144	(2S,3S,4S,5R)-5-(acetyloxy)-2-[(acetyloxy)methyl]-6-fluoro-4-methoxytetrahydro-2H-pyran-3-yl acetate	n/a	C₁₃H₁₉FO₈	详情	详情
(III)	54145	(2R,3R,4S,5S,6S)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-4-methoxytetrahydro-2H-pyran-3-yl acetate	n/a	C₄₁H₅₀O₁₄	详情	详情
(IV)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(V)	54146	(4aS,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-8-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ol	n/a	C₃₈H₄₈O₁₁	详情	详情
(VI)	54147	(4aS,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-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,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-7,8-dimethoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxine	n/a	C₃₉H₅₀O₁₁	详情	详情
(VII)	54148	(2S,3S,4S,5R,6S)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-2-(hydroxymethyl)-4,5-dimethoxytetrahydro-2H-pyran-3-ol	n/a	C₃₆H₄₆O₁₁	详情	详情
(VIII)	54149	(2S,3S,4S,5R,6S)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dimethoxytetrahydro-2H-pyran-3-ol	n/a	C₄₂H₆₀O₁₁Si	详情	详情
(IX)	36170	4-oxopentanoic acid	123-76-2	C₅H₈O₃	详情	详情
(X)	54150	(2S,3S,4R,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dimethoxytetrahydro-2H-pyran-3-yl 4-oxopentanoate	n/a	C₄₇H₆₆O₁₃Si	详情	详情
(XI)	54151	(2R,3S,4R,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-4,5-dimethoxy-3-[(4-oxopentanoyl)oxy]tetrahydro-2H-pyran-2-carboxylic acid	n/a	C₄₁H₅₀O₁₄	详情	详情
(XII)	54152	methyl (2R,3S,4S,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylate	n/a	C₃₇H₄₆O₁₂	详情	详情

合成路线2

The L-ioduronic acid methyl ester derivative (XII) is then converted into its D-glucuronic acid methyl ester counterpart (XIII) by epimerization with NaOMe in refluxing MeOH, followed by esterification with MeI and KHCO3 in DMF. Protection of the ester (XIII) with levulinic acid (IX) by means of DCC and DMAP in dioxane, followed by acetolysis of the anomeric center with sulfuric acid in acetic anhydride furnishes the disaccharide (XIV), which is then saponified with piperidine and subjected to reaction with trichloroacetonitrile and Cs2CO3 in THF to yield the imidate (XV). Glycosylation of the disaccharide (XII) with the imidate (XV) by means of trimethylsilyl triflate in CH2Cl2, followed by removal of the levulinoyl group by means of hydrazine acetate, furnishes the tetrasaccharide (XVI), which is coupled with the glucosyl trichloroacetimidate (XVIII) by means of trimethylsilyl trifluoromethanesulfonate in CH2Cl2 providing the pentasaccharide (XVII). Glucosyl imidate (XVIII) is prepared by methylation of 1,6-anhydroglucose (XIX) with MeI and NaH in DMF, followed by acetolysis with Ac2O/TFA to give compound (XX), which is treated with piperidine in THF and finally with trichloroacetonitrile in dichloromethane in the presence of Cs2CO3. The pentasaccharide (XVII) is deprotected by saponification with LiOH in THF/H2O2, and then hydrogenated over Pd/C in tert-butanol/water to provide a fully deprotected pentamer, which is finally subjected to sulfation with triethylamine sulfur trioxide complex in DMF and converted into the corresponding sodium salt by elution in a Dowex 50 XW4-Na+ or a Mono-Q anion-exchange column.

参考文献中间体

【1】 del Fresno, M.; Diaz-Ricart, M.; Idraparinux Sodium. Drugs Fut 2002, 27, 7, 639.
【2】 Basten, J.E.M.; van Boeckel, C.A.A.; Westerduin, P.; et al.; Feasible synthesis and biological properties of six "non-glycosamino" glycan analogues of the antithrombin III binding heparin pentasaccharide. Bioorg Med Chem 1994, 2, 11, 1267.
【3】 van Boeckel, C.A.A.; Petitou, M. (Akzo Nobel N.V.; Sanofi-Synthelabo); Carbohydrate derivs. comprising a trisaccharide unit. EP 0454220; JP 1992225994; US 5378829; US 5382570; US 5529985; US 5773605 .
【4】 Petitou, M.; van Boeckel, C.A.A. (Akzo Nobel N.V.; Sanofi-Synthelabo); Sulfated glycosaminoglycanoid derivs.. EP 0529715 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	36170	4-oxopentanoic acid	123-76-2	C₅H₈O₃	详情	详情
(XII)	54152	methyl (2R,3S,4S,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylate	n/a	C₃₇H₄₆O₁₂	详情	详情
(XIII)	54153	vmethyl (2S,3S,4S,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylate	n/a	C₃₇H₄₆O₁₂	详情	详情
(XIV)	54154	methyl (2S,3S,4R,5R,6R)-6-{[(2R,3R,4R,5R)-4,6-bis(acetyloxy)-2-[(acetyloxy)methyl]-5-(benzyloxy)tetrahydro-2H-pyran-3-yl]oxy}-4,5-dimethoxy-3-[(4-oxopentanoyl)oxy]tetrahydro-2H-pyran-2-carboxylate	n/a	C₃₃H₄₄O₁₇	详情	详情
(XV)	54155	methyl (2S,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	n/a	C₃₃H₄₂Cl₃NO₁₆	详情	详情
(XVI)	54156	methyl (2S,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)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-4,5-dimethoxy-2-(methoxycarbonyl	n/a	C₆₃H₈₀O₂₅	详情	详情
(XVII)	54158		n/a	C₇₄H₉₈O₃₁	详情	详情
(XVIII)	54157	{(2R,3S,4S,5R,6R)-3,4,5-trimethoxy-6-[(2,2,2-trichloroethanimidoyl)oxy]tetrahydro-2H-pyran-2-yl}methyl acetate	n/a	C₁₃H₂₀Cl₃NO₇	详情	详情
(XIX)	54159	(1R,2S,3S,4R,5R)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol	n/a	C₆H₁₀O₅	详情	详情
(XX)	54160	(3R,4S,5S,6R)-6-[(acetyloxy)methyl]-3,4,5-trimethoxytetrahydro-2H-pyran-2-yl acetate	n/a	C₁₃H₂₂O₈	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)