methyl (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】62241

【品名】methyl (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate

【CA登记号】

【分子式】C₁₄H₁₈O₈

【分子量】314.29212

【元素组成】C 53.5% H 5.77% O 40.72%

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：(VIII)

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

合成路线2

该中间体在本合成路线中的序号：(VIII)

10-Hydroxycamptothecin (IX) is nitrated with HNO3/H2SO4 and the resulting 9-nitro-10-hydroxycamptothecin (X) is treated with tosyl chloride to form the tosylate (XI). Palladium-catalyzed reduction of nitro tosylate (XI) gives rise to 9-aminocapmtothecin (XII). Amine (XII) is activated as the isocyanate (XIII) upon treatment with triphosgene (1) or alternatively as the aryl carbamate (XIV) employing p-nitrophenyl chloroformate. Coupling of either isocyanate (XIII) or carbamate (XIV) with p-hydroxybenzyl alcohol glucuronide (VIII) leads to adduct (XV). The methyl glucuronate ester (XV) is finally hydrolyzed to the target acid under anhydrous conditions by using potassium trimethylsilanolate.

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
(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
(IX)	13340	(4S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin	86639-52-3	C₂₀H₁₆N₂O₅	详情	详情
(X)	43901	(4S)-4-ethyl-4,9-dihydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione		C₂₀H₁₅N₃O₇	详情	详情
(XI)	43902	(4S)-4-ethyl-4-hydroxy-10-nitro-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylbenzenesulfonate		C₂₇H₂₁N₃O₉S	详情	详情
(XII)	44148	(4S)-10-amino-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione		C₂₀H₁₇N₃O₄	详情	详情
(XIII)	62243	(4S)-4-ethyl-4-hydroxy-10-isocyanato-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione		C₂₁H₁₅N₃O₅	详情	详情
(XIV)	62244	4-nitrophenyl (4S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-ylcarbamate		C₂₇H₂₀N₄O₈	详情	详情
(XV)	62245	methyl (2S,3S,4S,5R)-6-(4-{[({[(4S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl]amino}carbonyl)oxy]methyl}phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate		C₃₅H₃₃N₃O₁₃	详情	详情

Extended Information