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

【结构式】

【分子编号】44150

【品名】methyl 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 (20S)-camptothecin (I) with HOAc and H2O2 followed by light irradiation in H2SO4 yields hydroxy derivative (II), which is then nitrated by means of HNO3 and H2SO4 to afford compound (III). Sulfonation of (III) by reaction with p-TsCl (IV) in the presence of Et3N and DMAP in CH2Cl2 provides sulfonate (V), which is then subjected to reduction by treatment with Pd(OAc)2, PPh3 and triethylammoniumformate (HCOOH·Et3N) to give 9-aminocamptothecin (VI). Reaction of (VI) with nitrophenyl chloroformate (VII) in dioxane, followed by treatment with intermediate (VIII) and DMAP in acetonitrile, provides (IX). Alternatively, (IX) can also be obtained by first treatment of (VI) with triphosgene followed by reaction with intermediate (VIII) in pyridine and chromatographic purification. Finally, (IX) is treated with potassium trimethyl silanate (KOSiMe3) for methyl ester cleavage and acidified with HCl.

参考文献中间体

合成目标

【1】 Cabri, W.; et al.; A new high yield semisynthetic approach to (20S)-9-NH2-camptothecin based on a sequence of palladium-catalysed reductions. Tetrahedron Lett 1995, 36, 50, 9197.
【2】 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.
【3】 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
(A)	44149	bis(trichloromethyl) carbonate;Triphosgene	32315-10-9	C₃Cl₆O₃	详情	详情
(I)	10816	Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione	7689-03-4	C₂₀H₁₆N₂O₄	详情	详情
(II)	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
(III)	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
(IV)	13975	p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride	98-59-9	C₇H₇ClO₂S	详情	详情
(V)	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
(VI)	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
(VII)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(VIII)	44150	methyl 3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₁₄H₁₈O₈	详情	详情
(IX)	44151	methyl 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

合成路线2

该中间体在本合成路线中的序号：(VIII)

Intermediate (VIII) can be obtained as follows: Bromination of glucuronate derivative (X) by means of TiBr4 in CH2Cl2 followed by reaction with p-hydroxybenzaldehyde (XI) in acetonitrile in the presence of Ag2O affords derivative (XII), whose aldehyde moiety is then reduced by means of NaBH4 and silica gel in isopropanol/CHCl3 to provide benzyl alcohol (XIII). Finally, O-acetyl groups of (XIII) are cleaved by means of NaOMe in MeOH to furnish intermediate (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
(VIII)	44150	methyl 3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₁₄H₁₈O₈	详情	详情
(X)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(XI)	44154	methyl 3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-carboxylate		C₁₅H₂₀O₁₁	详情	详情
(XII)	44152	methyl 3,4,5-tris(acetoxy)-6-(4-formylphenoxy)tetrahydro-2H-pyran-2-carboxylate		C₂₀H₂₂O₁₁	详情	详情
(XIII)	44153	methyl 3,4,5-tris(acetoxy)-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₂₀H₂₄O₁₁	详情	详情

Extended Information