Synthesis of carbon‐14 labeled Taxol® (paclitaxel)

Abstract

SUMMARYReductive cleavage of the C13 side chain of Taxola (1, paclitaxel) followed by regioselective silylation gave 7-triethylsilylbaccatin 111 ( 4 ) . 3-0-Triethylsilylation of 5 and subsequent reaction with benzoyl chloride-C7-W gave azetidinone 7. Coupling of 4 and 7 followed by deprotection gave 1.26 g of Taxol@-N3'-W (11) having a specific activity of 26.5 mCilmmol and a radiochemical purity of 95%.Key words: TaxoP, paclitaxel, carbon-14 INTRODUCTIONThe diterpenoid TaxoP (1, paclitaxel)z continues to show promise as an effective anticancer agent.3-8 A number of researchers have reported preparations of various tritium-labeled taxols9-)1 which were used for a variety of pharmacological studies. Other reports have described the de novo synthesis of sub-milligram amounts of radiolabeled TaxoP (3H, '4C or dual labeled) from ~81112.13 or fungus14 cultures using appropriately labeled precursors. However, the preparation of a specifically labeled carbon-I4 TaxoP in synthetically useful quantities remains unreported. We required such a labeled TaxoP to support ongoing pharmacokinetic investigations and for use as a starting material for carbon-14-labeled prodrugs of Taxol@.ls In this paper we report the synthesis of gram quantities of Taxol@-N3'-'4C (1 1). D.G. Walker et a/. RESULTS AND DISCUSSIONThe requisite taxane component 4 was derived from TaxolB (1)2 by modified literature procedures (Scheme 1). Reductive cleavage of the C13 side chain16 was accomplished on reacting 1 with sodium borohydride in tetrahydrofuran (THF) / pH 7 phosphate buffer. Yields of baccatin 111 (2)16 were generally 75-80% after chromatographic purification, which removed minor amounts of 7-epi-baccatin 111 (3) produced under these conditions. Regioselective 7-Otriethylsilylation of 217 by reaction with excess triethylchlorosilane and imidazole in dichloromethane afforded gram quantities of 7-triethylsilylbaccatin 111 (4)17 after chromatographic purification. HOiii imidazole 4The C13 side chain synthon 718-21 was assembled as shown in Scheme 2. 3-0-Triethylsilylation of 522 proceeded smoothly in near quantitative yieM to afford 6, which was sufficiently pure for conversion to azetidinone 7. Thus, N-benzoylation of 6 was observed on reaction with benzoyl chloride -C7-74C,23 N,Ndiisopropylethylamine and a catalytic amount of 4-dimethylaminopyridine in dichloromethane. Care must be taken not Iff store crude 7 in vacuo at ambient temperature, since rapid conversion to a mixture of 8 and unidentifiable decomposition product(s) occurs. Yields consistently in the range of 80-85% (5 -> 7 )were observed when the process stream containing 7 was concentrated to near dryness, redissolved in minimal dichloromethane and immediately purified by flash chromatography over silica gel. Under these conditions, formation of 8 and decomposition were suppressed.C0upling18~19 of the lithium alkoxide of 4 with 7 (1.35 equiv) in THF gave 2'.7-bis(triethylsilyl)taxol-N3'-~4C (9) in good yield after chromatographic purification (Scheme 3). Hydrolysis of the triethyl...

Synthesis of deuterium‐labelled paclitaxel and its hydroxyl metabolite

“…25 The high yield was achieved by repeatedly adding osmium tetroxide and NMO. Treatment of (10) (11) in 7% yield, along with 80% unreacted starting material. Since the epimerization was essentially an equilibrium reaction, 26 reaction time cannot be longer than 1.5 h. Otherwise it will lead to the formation of other impurities.…”

“…[10][11][12][13][14][15][16] The chiral side chain of taxol contains phenylisoserine ester and b-lactam. For our synthesis, the [ 2 H 5 ]benzoyl group was introduced of (7) 0 -O-(t-butyldimethylsilyl)-6, 7-dehydropaclitaxel (9).…”

“…The preparation of the stable labelled versions of the title compounds with M15 was requested. Although 3 H-paclitaxel and 14 C-paclitaxel have been prepared for pharmacological studies, 10,11 the synthesis of its stable labelled internal standards has not been disclosed in detail. 12 In this paper, the synthetic routes to [ 2 H 5 ]paclitaxel and its 6a-hydroxyl metabolite are described in detail.…”

Hemisynthesis of [3′‐14C]‐Taxotere®

“…Taxola N3'-I4C was synthesized recently from [7-'4C] benzoylchloride and 7-triethylsilylbaccatin 111 (5). [3'-IJC]-Taxotkre@ labelled on the side chain was required by Rh6ne-Poulenc Rorer for metabolic studies.…”