　 -Drug Synthesis Database

【结构式】

【分子编号】65648

【品名】　

【CA登记号】　

【分子式】C₁₄H₂₄O₃

【分子量】240.34276

【元素组成】C 69.96% H 10.07% O 19.97%

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：(V)

Sagopilone is synthesized by the assembly of three modular building blocks, designated as segments A (V), B (II) and C (I). Wittig reaction of phosphonium salt (I) (segment C) with ketone (II) (segment B) in the presence of NaHMDS provides, after acidic hydrolysis of the tetrahydropyranyl protecting group, adduct (III) as a nearly equimolecular mixture of E/Z olefins. After chromatographic isolation of the target Z-isomer, Swern oxidation of the primary alcohol affords aldehyde (IV). This compound is then condensed with ketone (V) (segment A) in the presence of LDA and ZnCl2 to produce diastereoselectively the aldol adduct (VI). Subsequent acidic hydrolysis of the acetonide (VI) followed by protection of the free hydroxyls with TBDMSOTf and 2,6-lutidine generates the tetrasilyl ether (VII). The primary silyl ether of (VII) is then selectively removed by means of camphorsulfonic acid in MeOH/CH2Cl2, and the resulting alcohol is stepwise oxidized to carboxylic acid (VIII) by treatment with DMSO and oxalyl chloride followed by sodium chlorite in the presence of NaH2PO4 and 2-methyl-2-butene. Selective deprotection of the benzylic alcohol of (VIII) is accomplished by desilylation with TBAF, and the linear hydroxy acid is then cyclized to the key 16-membered macrolactone by means of 2,4,6-trichlorobenzoyl chloride (TCBCl) and DMAP under Yamaguchi conditions. After removal of the remaining silyl ether groups using hydrogen fluoride-pyridine complex in the presence of hexafluorosilicic acid, epoxidation of the endocyclic double bond with either dimethyldioxirane (DMDO) or methyl(trifluoromethyl)dioxirane (TFDO) furnishes the target epothilone (1, 2). Scheme 1.

参考文献中间体

合成目标

【1】 Klar, U., Schwede, W., Lichtner, R., Buchmann, B., Hoffmann, J., Skuballa, W. (Schering AG). 6-Alkenyl, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations. DE 19921086, EP 1173441, JP 2002543203, JP 2007224038, WO 2000066589.
【2】 Klar, U., Buchmann, B., Schwede, W., Skuballa, W., Hoffmann, J., Lichtner, R.B. Total synthesis and antitumor activity of ZK-EPO: The first fully synthetic epothilone in clinical development. Angew Chem Int Ed Engl 2006, 45(47): 7942-8.

中间体序号	中间体编号	分子式	供应商	用于合成
(I)	65644	C₃₅H₄₁INOPSSi	详情	详情
(II)	65645	C₁₃H₂₅O₃	详情	详情
(III)	65646	C₂₅H₄₁NO₂SSi	详情	详情
(IV)	65647	C₂₅H₃₉NO₂SSi	详情	详情
(V)	65648	C₁₄H₂₄O₃	详情	详情
(VI)	65649	C₃₉H₆₃NO₅SSi	详情	详情
(VII)	65650	C₅₄H₁₀₁NO₅SSi₄	详情	详情
(VIII)	65651	C₄₈H₈₅NO₆SSi₃	详情	详情
(IX)	65652	C₄₂H₆₉NO₅SSi₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The C1-C6 building block (V) (segment A) can be obtained as follows. Protection of (–)-pantolactone (X) as the tetrahydropyranyl ether (XI) using dihydropyran and pyridinium tosylate, followed by reduction of the lactone ring with DIBAL in cold toluene, gives the lactol (XII). Subsequent Wittig reaction of the cyclic hemiacetal (XII) with methylene triphenylphosphorane affords the hydroxy olefin (XIII), which is protected as the benzyl ether (XIV) by treatment with benzyl bromide and potassium tert-butoxide. Hydroboration of olefin (XIV) followed by quenching with alkaline H2O2 provides the primary alcohol (XV) as the major isomer, which is converted to the acetonide (XVI) by treatment with 2,2-dimethoxypropane and p-toluenesulfonic acid. After catalytic hydrogenolysis of the benzyl ether (XVI), the deprotected alcohol (XVII) is oxidized to aldehyde (XVIII) under Swern conditions. Then, addition of 3-butenylmagnesium bromide (XIX) to the aldehyde (XVIII) provides alcohol (XX), which is oxidized to the target ketone (V) by treatment with N-methylmorpholine N-oxide and a catalytic amount of tetrapropylammonium perruthenate (3). Scheme 2.

参考文献中间体

合成目标

【3】 Klar, U., Rohr, B., Kuczynski,F., Schwede, W., Berger, M., Skuballa, W., Buchmann, B. Efficient chiral pool synthesis of the C1-C6 fragment of epothilone. Synthesis 2005, (2): 301-5.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	65648			C₁₄H₂₄O₃	详情	详情
(X)	51427	D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone	599-04-2	C₆H₁₀O₃	详情	详情
(XI)	65653			C₁₁H₁₉O₄	详情	详情
(XII)	65654			C₁₁H₂₁O₄	详情	详情
(XIII)	65655			C₁₂H₂₃O₃	详情	详情
(XIV)	65656			C₁₉H₂₈O₃	详情	详情
(XV)	65657			C₁₉H₃₁O₄	详情	详情
(XVI)	65658			C₁₇H₂₆O₃	详情	详情
(XVII)	65659			C₁₀H₂₀O₃	详情	详情
(XVIII)	65660			C₁₀H₁₈O₃	详情	详情
(XIX)	35896	bromo(3-butenyl)magnesium	7103-09-5	C₄H₇BrMg	详情	详情
(XX)	65661			C₁₄H₂₆O₃	详情	详情

Extended Information