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【结 构 式】 
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【药物名称】Sagopilone, SH-Y03757A, ZK epothilone, ZK-219477, ZK-EPO 【化学名称】(1S,3S,7S,10R,11S,12S,16R)-10-Allyl-7,11-dihydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione 【CA登记号】305841-29-6 【 分 子 式 】C30H41NO6S 【 分 子 量 】543.7157 |
【开发单位】Bayer Schering Pharma (DE). 【药理作用】Microtubule-Stabilizing Agent, Epothilone, Oncolytic |
合成路线1
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
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.
| 【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 |
合成路线3
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4
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.
| 【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 |