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

【结构式】

【分子编号】17324

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

【CA登记号】7355-18-2

【分子式】C₁₅H₂₀O₁₁

【分子量】376.3172

【元素组成】C 47.88% H 5.36% O 46.77%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

The two major metabolites of raloxifene, the glucuronide conjugates (VI) and (VIII) are synthesized as follows: The partial silylation of raloxifene (I) with tert-butyldimethylsilyl chloride (TBDMS-Cl) by means of dimethylaminopyridine (DMAP) in THF/DMF gives a mixture of the monosilylated compounds (II) and (III), which are separated by chromatography. Compounds (II) and (III) are independently condensed with methyl 1,2,3,4-tetra-O-acetyl-D-glucuronate (IV) by means of BF3.OEt2 in dichloromethane yielding protected glucuronides (V) and (VII), respectively. Finally, both compounds are deprotected by a treatment first with LiOH in dioxane to hydrolyzed the ester groups, and then with tetrabutylammonium fluoride in THF to eliminate the silyl groups, thus obtaining the desired metabolites (VI) and (VIII), respectively.

参考文献中间体

合成目标

【1】 Glasebrook, A.L.; Frolik, C.A.; Dodge, J.A.; Cho, S.; Phillips, D.L.; Lugar, C.W.; Osborne, J.J.; Synthesis and estrogen receptor binding affinities of the major human metabolites of raloxifene (LY139481). Bioorg Med Chem Lett 1997, 7, 8, 993.
【2】 Dodge, J.A.; Stocksdale, M.G.; Jones, C.D.; A chemical probe for the estrogen receptor: Synthesis of the H-3 isotopomer of raloxifene. J Label Compd Radiopharm 1995, 36, 1, 43.

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)	17321	[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-(2-piperidinoethoxy)phenyl]methanone		C₂₈H₂₇NO₄S	详情	详情
(II)	17322	[6-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₄₁NO₄SSi	详情	详情
(III)	17323	[2-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-6-hydroxy-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₄₁NO₄SSi	详情	详情
(IV)	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
(V)	17325	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetoxy)-6-[4-(6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-2-yl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₄₁H₄₃NO₁₃S	详情	详情
(VI)	17326	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetoxy)-6-[(2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]tetrahydro-2H-pyran-2-carboxylate		C₄₁H₄₃NO₁₃S	详情	详情
(VII)	17327	(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[4-(6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-2-yl)phenoxy]tetrahydro-2H-pyran-2-carboxylic acid		C₃₄H₃₅NO₁₀S	详情	详情
(VIII)	17328	(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[(2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]tetrahydro-2H-pyran-2-carboxylic acid		C₃₄H₃₅NO₁₀S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

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