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【结 构 式】 
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【分子编号】10717 【品名】methyl (2S)-2-amino-2-phenylethanoate 【CA登记号】 |
【 分 子 式 】C9H11NO2 【 分 子 量 】165.19188 【元素组成】C 65.44% H 6.71% N 8.48% O 19.37% |
合成路线1
该中间体在本合成路线中的序号：(II)A new method for the synthesis of paclitaxel side chain has been developed: The esterification of (S)-phenylglycine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is acylated with benzoyl chloride and pyridine to the benzoyl derivative (III). The reduction of (III) with dibutylaluminum hydride (DIBAL) in toluene yields the corresponding aldehyde (IV), which is condensed with 2-(trimethylsilyl)thiazole (V) by means of tetrabutylammonium fluoride (TBAF) to afford the (1R,2S)-N-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]benzamide (VI) with a 95% enantiomeric purity. The cyclization of (VI) with 2,2-dimethoxypropane (VII) catalyzed by camphosulfonic acid (CSA) gives (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyl-5-(2-thiazolyl)oxazolidine (VIII), which is treated with methyl trifluoromethanesulfonate to afford (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carbaldehyde (IX). Finally, this compound is oxidized with KMnO4 in tert-butanol/aqueous potassium phosphate buffer to yield (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid (X), the side chain of paclitaxel suitably protected.
| 【1】 Semola, T.; Dondoni, A.; Perrone, D.; Synthesis of Taxol and Taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of L-phenylglycine. Synthesis 1995, 2, 2, 181. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| (I) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 | |
| (III) | 10718 | methyl (2S)-2-(benzoylamino)-2-phenylethanoate | C16H15NO3 | 详情 | 详情 | |
| (IV) | 10719 | N-[(1S)-2-Oxo-1-phenylethyl]benzamide | C15H13NO2 | 详情 | 详情 | |
| (V) | 10720 | 2-(Trimethylsilyl)-1,3-thiazole | 79265-30-8 | C6H11NSSi | 详情 | 详情 |
| (VI) | 10721 | N-[(1S,2R)-2-Hydroxy-1-phenyl-2-(1,3-thiazol-2-yl)ethyl]benzamide | C18H16N2O2S | 详情 | 详情 | |
| (VII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VIII) | 10723 | [(4S,5R)-2,2-Dimethyl-4-phenyl-5-(1,3-thiazol-2-yl)-1,3-oxazolidin-3-yl](phenyl)methanone | C21H20N2O2S | 详情 | 详情 | |
| (IX) | 10724 | (4S,5R)-3-Benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carbaldehyde | C19H19NO3 | 详情 | 详情 | |
| (X) | 10725 | (4S,5R)-3-Benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carboxylic acid | C19H19NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)A new method for the synthesis of the docetaxel side-chain has been reported: The esterification of (S)-phenylglycine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is acylated with tert-butoxycarbonyl anhydride to the tert-butoxycarbonyl derivative (III). The reduction of (III) with dibutylaluminum hydride (DIBAL) in toluene yields the corresponding aldehyde (IV), which is condensed with 2-(trimethylsilyl)thiazole (V) by means of tetrabutylammonium fluoride (TBAF) to afford the (1R,2S)-N-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]carbamic acid tert-butyl ester (VI) with 88% enantiomeric purity. The cyclization of (VI) with 2,2-dimethoxypropane (VII) catalyzed by camphosulfonic acid (CSA) gives (4S,5R)-3-(tert-butoxycarbonyl)-2,3-dimethyl-4-phenyl-5-(2-thiazolyl)ox azolidine (VIII), which is treated with methyl trifluoromethanesulfonate to afford (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb aldehyde (IX). Finally, this compound is oxidized with KMnO4 in tert-butanol/aqueous potassium phosphate buffer to yield the corresponding carboxylic acid, the (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb oxylic acid (X), the side-chain of taxotere suitably protected.
| 【1】 Semola, T.; Dondoni, A.; Perrone, D.; Synthesis of Taxol and Taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of L-phenylglycine. Synthesis 1995, 2, 2, 181. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 | |
| (I) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 | |
| (III) | 12485 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoate | C14H19NO4 | 详情 | 详情 | |
| (IV) | 45428 | tert-butyl (1S)-2-oxo-1-phenylethylcarbamate | C13H17NO3 | 详情 | 详情 | |
| (V) | 10720 | 2-(Trimethylsilyl)-1,3-thiazole | 79265-30-8 | C6H11NSSi | 详情 | 详情 |
| (VI) | 12488 | tert-butyl N-[(1S,2R)-2-hydroxy-1-phenyl-2-(1,3-thiazol-2-yl)ethyl]carbamate | C16H20N2O3S | 详情 | 详情 | |
| (VII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VIII) | 12490 | tert-butyl (4S,5R)-2,2-dimethyl-4-phenyl-5-(1,3-thiazol-2-yl)-1,3-oxazolane-3-carboxylate | C19H24N2O3S | 详情 | 详情 | |
| (IX) | 12491 | tert-butyl (4S,5R)-5-formyl-2,2-dimethyl-4-phenyl-1,3-oxazolane-3-carboxylate | C17H23NO4 | 详情 | 详情 | |
| (X) | 12492 | (4S,5R)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-4-phenyl-1,3-oxazolane-5-carboxylic acid | C17H23NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The esterification of L-phenylglycine (I) with AcCl and methanol gives the methyl ester (II), which is N-protected by means of Boc2O and TEA to yield the N-Boc derivative (III). The reduction of (III) with NaBH4 in ethanol/THF affords the alcohol (IV), which is oxidized by means of (COCl)2 and DMSO to provide the carbaldehyde (V). The reaction of (V) with vinylmagnesium bromide (VI) in THF gives the allyl alcohol (VII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (VIII). The alkylation of (VIII) with allyl bromide (IX) and NaH in DMF affords the N-allyl derivative (X), which is desilylated by means of TBAF and AcOH in THF to provide the allyl alcohol (XI). The ring closing metathesis reaction of (XI) with a Grubbs' catalyst in dichloromethane gives the tetrahydropyridine (XII), which is treated with H2 over Pd/C in ethanol to yield the chiral protected piperidine (XIII). The condensation of (XIII) with 3,5-bis(trifluoromethyl)benzyl bromide (XIV) by means of NaH in DMF affords the benzyl ether (XV), which is finally deprotected with TFA to provide the target piperidine.
| 【1】 Bhaskar, G.; Rao, B.V.; Stereoselective synthesis of L-733,060. Tetrahedron Lett 2003, 44, 5, 915. |
| 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) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 | |
| (III) | 12485 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoate | C14H19NO4 | 详情 | 详情 | |
| (IV) | 59225 | (R)-N-(tert-Butoxycarbonyl)-phenylglycinol; N-t-BOC-D-phenylglycinol | 102089-74-7 | C13H19NO3 | 详情 | 详情 |
| (V) | 45428 | tert-butyl (1S)-2-oxo-1-phenylethylcarbamate | C13H17NO3 | 详情 | 详情 | |
| (VI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (VII) | 64501 | tert-butyl (1S,2S)-2-hydroxy-1-phenyl-3-butenylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (VIII) | 64502 | tert-butyl (1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenylcarbamate | C21H35NO3Si | 详情 | 详情 | |
| (IX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (X) | 64503 | tert-butyl allyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenyl)carbamate | C24H39NO3Si | 详情 | 详情 | |
| (XI) | 64504 | tert-butyl allyl[(1S,2S)-2-hydroxy-1-phenyl-3-butenyl]carbamate | C18H25NO3 | 详情 | 详情 | |
| (XII) | 64505 | tert-butyl (2S,3S)-3-hydroxy-2-phenyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (XIII) | 64499 | tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (XIV) | 27677 | 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene | 32247-96-4 | C9H5BrF6 | 详情 | 详情 |
| (XV) | 64500 | tert-butyl (2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenyl-1-piperidinecarboxylate | C25H27F6NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)The Darzen's condensation of 4-iodoacetophenone (I) with methyl chloroacetate (II) in the presence of NaOMe afforded the glycidic ester (III), which was further hydrolyzed to the corresponding glycidic acid (IV) with NaOH in aqueous ethanol. Subsequent decarboxylation of (IV) under acidic conditions furnished 2-(4-iodophenyl)propionaldehyde (V). After oxidation of aldehyde (V) with sodium chlorite, the resultant carboxylic acid was converted to the corresponding zinc salt (VI) upon treatment with ZnCl2 and NaOH. Coupling of aryl iodide (VI) with the Grignard reagent (VIII) (prepared from 2-bromo-3-methylthiophene (VII)) in the presence of PdCl2 gave rise to the racemic biarylpropionic acid (IX)). The title (R)-enantiomer was then resolved via formation of the diastereoisomeric salts with D-phenylglycine methyl ester (X)
| 【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |
| 【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 . |
| 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) | 51497 | 4'-Iodoacetophenone; 4-Iodoacetophenone; 1-(4-Iodophenyl)ethanone | 13329-40-3 | C8H7IO | 详情 | 详情 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 62683 | methyl 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylate | C11H11IO3 | 详情 | 详情 | |
| (IV) | 62684 | 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylic acid | C10H9IO3 | 详情 | 详情 | |
| (V) | 62685 | 2-(4-iodophenyl)propanal | C9H9IO | 详情 | 详情 | |
| (VI) | 62686 | C18H16I2O4Zn | 详情 | 详情 | ||
| (VII) | 12443 | 2-Bromo-3-methylthiophene | 14282-76-9 | C5H5BrS | 详情 | 详情 |
| (VIII) | 36973 | bromo(3-methyl-2-thienyl)magnesium | C5H5BrMgS | 详情 | 详情 | |
| (IX) | 62687 | 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid | C14H14O2S | 详情 | 详情 | |
| (X) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 |