methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】17580

【品名】methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate

【CA登记号】

【分子式】C₁₃H₁₇BrO₉

【分子量】397.17658

【元素组成】C 39.31% H 4.31% Br 20.12% O 36.25%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

1) The oxidation of tasosartan (V) with KMnO4 and NaOH in water gives metabolite (I). 2) The condensation of tasosartan (V) with 2,3,4-tri-O-acetyl-1alpha-bromo-1-deoxy-D-glucopyranosyluronic acid methyl ester (VI) by means of KOH in refluxing acetone gives the acetylated glucuronide methyl ester (VII), which is deacetylated with KCN in methanol yielding glucuronide methyl ester (VIII). Finally, this compound is hydrolyzed with NaOH in methanol to afford metabolite (II).

参考文献中间体

合成目标

【1】 Ellingboe, J.W.; Collini, M.D.; Quagliato, D.; Chen, J.; Antane, M.; Schmid, J.; Hartupee, D.; White, V.; Park, C.H.; Tanikella, T.; Bagli, J.F.; Metabolites of the angiotensin II antagonist tasosartan: The importance of a second acidic group. J Med Chem 1998, 41, 22, 4251.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	26023	5-hydroxy-2,4-dimethyl-8-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one	C₂₃H₂₁N₇O₂	详情	详情
(II)	26024	sodium (2S,3S,4S,5R,6R)-6-[5-(4'-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl]methyl][1,1'-biphenyl]-2-yl)-2H-1,2,3,4-tetraazol-2-yl]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate	C₂₉H₂₈N₇NaO₇	详情	详情
(V)	26025	2,4-dimethyl-8-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one	C₂₃H₂₁N₇O	详情	详情
(VI)	17580	methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate	C₁₃H₁₇BrO₉	详情	详情
(VII)	26026	methyl (2S,3R,4S,5R,6R)-3,4,5-tris(acetoxy)-6-[5-(4'-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl]methyl][1,1'-biphenyl]-2-yl)-2H-1,2,3,4-tetraazol-2-yl]tetrahydro-2H-pyran-2-carboxylate	C₃₆H₃₇N₇O₁₀	详情	详情
(VIII)	26027	methyl (2S,3S,4S,5R,6R)-6-[5-(4'-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl]methyl][1,1'-biphenyl]-2-yl)-2H-1,2,3,4-tetraazol-2-yl]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate	C₃₀H₃₁N₇O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The synthesis of the acyl glucuronide of ML-3000 has been described: The cleavage of the lactone ring of D-glucuronic acid gamma-lactone (I) gives the bromide derivative (II), which is treated with silver oxide and benzyl alcohol to yield compound (III). The methanolysis of (III) with sodium methoxide in methanol, followed by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords silylated compound (IV). The hydrolysis of the ester group of (IV) with NaOH in THF/water, followed by reesterification with diethyl chlorophosphate, 2,2,2-trichloroehanol and DMAP gives the silylated trichloroethyl ester (V), which is debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate yielding D-glucuronate (VI). The esterification of the acid group of ML-3000 (VII) with (VI) by means of triphenylphosphine and DIAD in THF affords the corresponding ester (VIII), which is finally deprotected first with Zn and KH2PO4 to eliminate the trichloroethyl group, and then with THF in acetonitrile to eliminate the silyl groups. The product wasisolated as a 1:2 mixture of the alpha- and beta-anomers.

参考文献中间体

合成目标

【1】 Ries, M.; Kirschning, A.; Albrecht, W.; Domann, S.; Arnold, P.; Laufer, S.; Martin, W.; Synthesis and biological identification of the acyl glucuronide of the antiinflammatory drug ML-3000. Bioorg Med Chem Lett 1997, 7, 7, 903.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17579	(1S,2R,3S,4R,5S)-2,3-bis(acetoxy)-7-oxo-6,8-dioxabicyclo[3.2.1]oct-4-yl acetate	C₁₂H₁₄O₉	详情	详情
(II)	17580	methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate	C₁₃H₁₇BrO₉	详情	详情
(III)	17581	methyl (2S,3R,4S,5R,6R)-3,4,5-tris(acetoxy)-6-(benzyloxy)tetrahydro-2H-pyran-2-carboxylate	C₂₀H₂₄O₁₀	详情	详情
(IV)	17582	methyl (2S,3R,4S,5R,6R)-6-(benzyloxy)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-carboxylate	C₃₂H₆₀O₇Si₃	详情	详情
(V)	17583	2,2,2-trichloroethyl (2S,3R,4S,5R,6R)-6-(benzyloxy)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-carboxylate	C₃₃H₅₉Cl₃O₇Si₃	详情	详情
(VI)	17584	2,2,2-trichloroethyl (2S,3R,4S,5R)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxytetrahydro-2H-pyran-2-carboxylate	C₂₆H₅₃Cl₃O₇Si₃	详情	详情
(VII)	17585	2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid	C₂₃H₂₂ClNO₂	详情	详情
(VIII)	17586	2,2,2-trichloroethyl (2S,3R,4S,5R)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]-6-([2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetyl]oxy)tetrahydro-2H-pyran-2-carboxylate	C₄₉H₇₃Cl₄NO₈Si₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Treatment of glucuronic acid gamma-lactone (I) with sodium methoxide in methanol affords methyl glucuronate (II), which is further acylated by acetic anhydride to form the tetraacetate ester (III). Bromination of (III) with TiBr4, followed by coupling of the resultant bromide (IV) with p hydroxybenzaldehyde (V) in the presence of Ag2O yields the peracetylated glucuronide (VI). Aldehyde (VI) reduction employing NaBH4 in the presence of silica gel leads to the benzyl alcohol (VII). The acetate ester groups of (VII) are then removed with sodium methoxide in methanol to furnish (VIII).

参考文献中间体

合成目标

【1】 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623.
【2】 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 .

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)	18369	(3S,3aR,6R,6aR)-3,5,6-trihydroxytetrahydrofuro[3,2-b]furan-2(3H)-one	32449-92-6	C₆H₈O₆	详情	详情
(II)	62238	methyl (2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate		C₇H₁₂O₇	详情	详情
(III)	17324	methyl (2S,3R,4S,5R)-3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-carboxylate	7355-18-2	C₁₅H₂₀O₁₁	详情	详情
(IV)	17580	methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate		C₁₃H₁₇BrO₉	详情	详情
(V)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(VI)	62239	methyl (2S,3R,4S,5R)-3,4,5-tris(acetyloxy)-6-(4-formylphenoxy)tetrahydro-2H-pyran-2-carboxylate		C₂₀H₂₂O₁₁	详情	详情
(VII)	62240	methyl (2S,3R,4S,5R)-3,4,5-tris(acetyloxy)-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₂₀H₂₄O₁₁	详情	详情
(VIII)	62241	methyl (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₁₄H₁₈O₈	详情	详情

Extended Information