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【结 构 式】 
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【分子编号】65644 【品名】 【CA登记号】 |
【 分 子 式 】C35H41INOPSSi 【 分 子 量 】709.746412 【元素组成】C 59.23% H 5.82% I 17.88% N 1.97% O 2.25% P 4.36% S 4.52% Si 3.96% |
合成路线1
该中间体在本合成路线中的序号：(I)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.
| 【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 | 品名 | CAS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：(I)The preparation of segment C (I) can be accomplished as follows. One-pot treatment of 4-chloro-3-nitrobenzoic acid (XXVIII) with Na2S and Ac2O/AcOH gives 2-methylbenzothiazole-5-carboxylic acid (XXIX), which is subsequently reduced with LiAlH4 in boiling THF followed by reoxidation of the obtained alcohol (XXX) with DMSO and SO3-pyridine complex to give the aldehyde (XXXI) (2). In an alternative procedure, aldehyde (XXXI) is produced by coupling of 5-chloro-2-methylbenzothiazole (XXXII) with acrylic acid in the presence of Pd2(dba)3 and NiBr2 followed by oxidative cleavage of the resulting arylacrylic acid (XXXIII) with OsO4 and NaIO4 (1). Aldol condensation of aldehyde (XXXI) with the chiral N-acetyloxazolidinone (XXXIV) by means of BuLi and ZnCl2 produces adduct (XXXV) as the major diastereoisomer. After protection of the free hydroxyl group of (XXXV) as the corresponding tert-butyldimethylsilyl ether (XXXVI), the chiral auxiliary group is removed by treatment with titanium ethoxide in boiling EtOH. The resulting ethyl ester (XXXVII) is then reduced to alcohol (XXXVIII) employing DIBAL in cold toluene/CH2Cl2. Subsequent reaction of alcohol (XXXVIII) with I2 and PPh3 provides the alkyl iodide (XXXIX), which is then displaced with triphenylphosphine in hot toluene, producing the target phosphonium salt (I) (1, 2). Scheme 4.
| 【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 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 65644 | C35H41INOPSSi | 详情 | 详情 | ||
| (XXVIII) | 14485 | 3-nitro-4-chlorobenzoic acid; 4-chloro-3-nitrobenzoic acid | 96-99-1 | C7H4ClNO4 | 详情 | 详情 |
| (XXIX) | 65667 | 2-Methyl-1,3-Benzothiazole-5-Carboxylic Acid | 24851-69-2 | C9H7NO2S | 详情 | 详情 |
| (XXX) | 65668 | (2-Methyl-1,3-benzothiazol-5-yl)methanol | 32770-97-1 | C9H9NOS | 详情 | 详情 |
| (XXXI) | 65669 | 2-Methyl-1,3-Benzothiazole-5-Carbaldehyde | 20061-46-5 | C9H7NOS | 详情 | 详情 |
| (XXXII) | 65670 | 5-chloro-2-methyl-1,3-benzothiazole | C8H6ClNS | 详情 | 详情 | |
| (XXXIII) | 65671 | C11H9NO2S | 详情 | 详情 | ||
| (XXXIV) | 65672 | C12H13NO3 | 详情 | 详情 | ||
| (XXXV) | 65673 | C21H20N2O4S | 详情 | 详情 | ||
| (XXXVI) | 65674 | C27H34N2O4SSi | 详情 | 详情 | ||
| (XXXVII) | 65675 | C19H29NO3SSi | 详情 | 详情 | ||
| (XXXVIII) | 65676 | C17H27NO2SSi | 详情 | 详情 | ||
| (XXXIX) | 65677 | C17H26INOSSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The intermediate (S)-adamantylglycine (I) can be prepared as follows. Reduction of adamantane-1-carboxylic acid (XVI) using LiAlH4 in THF gives the primary alcohol (XVII), which is oxidized to aldehyde (XVIII) under Swern conditions. Adamantane-1-carbaldehyde (XVIII) is then condensed with (R)-phenylglycinol (XIX) and KCN in the presence of NaHSO3 to yield the chiral aminonitrile (XX). After acidic hydrolysis of nitrile (XX) to the corresponding amino acid (XXI), the chiral auxiliary group is removed by hydrogenolysis over Pearlman’s catalyst to furnish intermediate (I) (1, 6). Scheme 2.
| 【1】 Robl, J.A., Sulsky, R.B., Betebenner, D.A., Magnin, D.R., Hamann, L.G., Augeri, D.J. (Bristol-Myers Squibb Co.). Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method. EP 1261586, JP 2003531118, US 6395767, WO 0168603. |
| 【6】 Augeri, D.J., Robl, J.A., Betebenner, D.A. et al. Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005, 48(15): 5025-37. |
| 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) | 65644 | C35H41INOPSSi | 详情 | 详情 | ||
| (XVI) | 65693 | 1-Adamantanecarboxylic acid; Adamantane-1-carboxylic acid; Tricyclo[3.3.1.1(3,7)]decan-1-Carboxylic acid | 828-51-3 | C11H16O2 | 详情 | 详情 |
| (XVII) | 65694 | 1-Adamantanemethanol; 1-(Hydroxymethyl)adamantane; 1-Tricyclo[3.3.1.1(3,7)]decanemethanol | 770-71-8 | C11H18O | 详情 | 详情 |
| (XVIII) | 65695 | 1-Adamantylcarboxaldehyde; Tricyclo[3.3.1.1(3,7)]decane-1-carboxaldehyde; 1-Formyladamantane | 2094-74-8 | C11H16O | 详情 | 详情 |
| (XIX) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XX) | 65696 | (alphaS)-alpha-[[(1R)-2-Hydroxy-1-phenylethyl]amino]-tricyclo[3.3.1.1(3,7)]decane-1-acetonitrile | 361441-95-4 | C20H26N2O | 详情 | 详情 |
| (XXI) | 65697 | C20H27NO3 | 详情 | 详情 |