　 -Drug Synthesis Database

【结构式】

【分子编号】65645

【品名】　

【CA登记号】　

【分子式】C₁₃H₂₅O₃

【分子量】229.3397

【元素组成】C 68.08% H 10.99% O 20.93%

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：(II)

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：(II)

The preparation of the C7-C12 building block (II) (segment B) is performed as follows. Protection of methyl 3-hydroxy-2(R)-methylpropionate by means of dihydropyran and p-toluenesulfonic acid in CH2Cl2 gives the tetrahydropyranyl ether (XXII), which is then reduced with LiAlH4 in Et2O to yield alcohol (XXIII) and derivatized to tosylate (XXIV) under the usual conditions. Reaction of 3-methyl-3-buten-1-ol (XXV) with N-bromosuccinimide and triphenylphosphine in CH2Cl2 affords the butenyl bromide (XXVI) which, after conversion to the corresponding Grignard reagent, is coupled with tosylate (XXIV) in the presence of catalytic Li2CuCl4 leading to adduct (XXVII). Then, dihydroxylation of olefin (XXVII) and subsequent oxidative cleavage employing OsO4 and NaIO4 gives the desired ketone (II) (2). Scheme 3.

参考文献中间体

合成目标

【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	品名	CAS号	分子式	供应商	用于合成
(II)	65645			C₁₃H₂₅O₃	详情	详情
(XXI)	14965	methyl 3-hydroxy-2-methylpropanoate; METHYL (S)-(+)-3-HYDROXY-2-METHYLPROPIONATE	80657-57-4	C₅H₁₀O₃	详情	详情
(XXII)	65662			C₁₀H₁₉O₄	详情	详情
(XXIII)	65663			C₉H₁₈O₃	详情	详情
(XXIV)	65664			C₁₀H₂₀O₅S	详情	详情
(XXV)	47474	3-methyl-3-buten-1-ol	763-32-6	C₅H₁₀O	详情	详情
(XXVI)	65665	4-Bromo-2-methyl-1-butene; 1-Bromo-3-methyl-3-butene; 2-Methyl-4-bromo-1-butene; 3-Methyl-3-butenyl bromide	20038-12-4	C₅H₉Br	详情	详情
(XXVII)	65666			C₁₄H₂₆O₂	详情	详情

Extended Information