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【结 构 式】 
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【分子编号】36505 【品名】(methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate 【CA登记号】 |
【 分 子 式 】C27H32ClNO6S 【 分 子 量 】534.07292 【元素组成】C 60.72% H 6.04% Cl 6.64% N 2.62% O 17.97% S 6% |
合成路线1
该中间体在本合成路线中的序号：(XVII)The intermediate epoxyamide (XVIII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensa-tion of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide.
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)The deprotection of the carbamate (XVIII) by means of TFA gives the free aminoester (XIX), which is reprotected with Fmoc-Cl and NaHCO3 yielding the acid (XX). The esterification of the hydroxy group of he intermediate (XVII) with the acid group of (XX) by means of EDC affords the expected ester (XXI). The oxidation of the methylsulfanyl group of (XXI) with oxone affords the corresponding methylsulfonylmethyl ester (XXII), which is cyclized by means of piperidine in DMF to give the macrocyclic epoxide (XXIII). Finally, this compound is treated with 12 N HCl in dimethoxyethane/water.
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 | |
| (XVIII) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 | |
| (XIX) | 36506 | (2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoic acid | C11H21NO4 | 详情 | 详情 | |
| (XX) | 36507 | (2S)-2-[(3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,2-dimethylpropanoyl)oxy]-4-methylpentanoic acid | C26H31NO6 | 详情 | 详情 | |
| (XXI) | 36508 | (methylsulfanyl)methyl (9S,12S,14E,18R)-18-(3-chloro-4-methoxybenzyl)-1-(9H-fluoren-9-yl)-9-isobutyl-6,6-dimethyl-3,7,10,16-tetraoxo-12-[(1R)-1-[(2R,3S)-3-phenyloxiranyl]ethyl]-2,8,11-trioxa-4,17-diaza-14-nonadecen-19-oate | C53H61ClN2O11S | 详情 | 详情 | |
| (XXII) | 36509 | (methylsulfonyl)methyl (9S,12S,14E,18R)-18-(3-chloro-4-methoxybenzyl)-1-(9H-fluoren-9-yl)-9-isobutyl-6,6-dimethyl-3,7,10,16-tetraoxo-12-[(1R)-1-[(2R,3S)-3-phenyloxiranyl]ethyl]-2,8,11-trioxa-4,17-diaza-14-nonadecen-19-oate | C53H61ClN2O13S | 详情 | 详情 | |
| (XXIII) | 63540 | (3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-16-{(1R)-1-[(2R,3R)-3-phenyloxiranyl]ethyl}-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone | C36H45ClN2O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)The intermediate epoxyamide (XVII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensation of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide (XVII).
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)The deprotection of the carbamate (XVIII) by means of TFA gives the free aminoester (XIX), which is reprotected with Fmoc-Cl and NaHCO3 yielding the acid (XX). The esterification of the hydroxy group of he intermediate (XVII) with the acid group of (XX) by means of EDC affords the expected ester (XXI). The oxidation of the methylsulfanyl group of (XXI) with oxone affords the corresponding methylsulfonylmethyl ester (XXII), which is finally cyclized by means of piperidine in DMF.
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 | |
| (XVIII) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 | |
| (XIX) | 36506 | (2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoic acid | C11H21NO4 | 详情 | 详情 | |
| (XX) | 36507 | (2S)-2-[(3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,2-dimethylpropanoyl)oxy]-4-methylpentanoic acid | C26H31NO6 | 详情 | 详情 | |
| (XXI) | 36508 | (methylsulfanyl)methyl (9S,12S,14E,18R)-18-(3-chloro-4-methoxybenzyl)-1-(9H-fluoren-9-yl)-9-isobutyl-6,6-dimethyl-3,7,10,16-tetraoxo-12-[(1R)-1-[(2R,3S)-3-phenyloxiranyl]ethyl]-2,8,11-trioxa-4,17-diaza-14-nonadecen-19-oate | C53H61ClN2O11S | 详情 | 详情 | |
| (XXII) | 36509 | (methylsulfonyl)methyl (9S,12S,14E,18R)-18-(3-chloro-4-methoxybenzyl)-1-(9H-fluoren-9-yl)-9-isobutyl-6,6-dimethyl-3,7,10,16-tetraoxo-12-[(1R)-1-[(2R,3S)-3-phenyloxiranyl]ethyl]-2,8,11-trioxa-4,17-diaza-14-nonadecen-19-oate | C53H61ClN2O13S | 详情 | 详情 |