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【结 构 式】 
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【分子编号】26469 【品名】methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoate 【CA登记号】 |
【 分 子 式 】C12H21NO5 【 分 子 量 】259.30248 【元素组成】C 55.58% H 8.16% N 5.4% O 30.85% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Taxane intermediates (XIII) and (XIV) were prepared by two related ways. Wittig condensation of cyclopropanecarboxaldehyde (I) with methoxycarbonylmethylenetriphenyl phosphorane (II) gave methyl trans-cyclopropylacrylate (III). This was oxidized with potassium ferricyanide in the presence of OsO4 and the chiral catalyst 1,4-bis(9-O-dihydroquinidyl)phthalazine to furnish (2S,3R)-diol (IV). After conversion of (IV) to tosylate (V), its cyclization by means of K2CO3 produced epoxide (VI). Subsequent epoxide opening with NaN3 gave azide (VII), which was hydrogenated in the presence of Pd/C and di tert-butyl dicarbonate to furnish carbamate (VIII). Treatment of (VIII) with isopropenyl methyl ether (IX) and pyridinium tosylate, followed by ester hydrolysis, produced oxazolidine (X). This was coupled to protected taxane (XI) by means of DCC and DMAP to provide ester (XII). Oxazolidine hydrolysis in (XII) with formic acid, followed by reprotection of the amine with Boc2O, furnished intermediate (XIII). Optionally, the trichloroethoxycarbonyl groups of (XIII) were removed upon treatment with Zn and AcOH to produce intermediate (XIV).
| 【1】 Tsujihari, K.; Hashiyama, T.; Ohashi, M.; Nakanishi, N. (Tanabe Seiyaku Co., Ltd.); Baccatin derivs. and processes for preparing the same. CA 2162759; EP 0712854; JP 1997151181; US 5589502 . |
| 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) | 26463 | cyclopropanecarbaldehyde | 1489-69-6 | C4H6O | 详情 | 详情 |
| (II) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (III) | 26464 | methyl (E)-3-cyclopropyl-2-propenoate | C7H10O2 | 详情 | 详情 | |
| (IV) | 26465 | methyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate | C7H12O4 | 详情 | 详情 | |
| (V) | 26466 | methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-[[(4-methylphenyl)sulfonyl]oxy]propanoate | C14H18O6S | 详情 | 详情 | |
| (VI) | 26467 | methyl (2R,3R)-3-cyclopropyl-2-oxiranecarboxylate | C7H10O3 | 详情 | 详情 | |
| (VII) | 26468 | methyl (2R,3S)-3-azido-3-cyclopropyl-2-hydroxypropanoate | C7H11N3O3 | 详情 | 详情 | |
| (VIII) | 26469 | methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoate | C12H21NO5 | 详情 | 详情 | |
| (IX) | 26470 | 3-methoxy-1-butene | C5H10O | 详情 | 详情 | |
| (X) | 26471 | (4S,5R)-3-(tert-butoxycarbonyl)-4-cyclopropyl-2,2-dimethyl-1,3-oxazolidine-5-carboxylic acid | C14H23NO5 | 详情 | 详情 | |
| (XI) | 23892 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C35H38Cl6O14 | 详情 | 详情 | |
| (XII) | 26472 | methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate | C49H59Cl6NO18 | 详情 | 详情 | |
| (XIII) | 26473 | methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate | C46H55Cl6NO18 | 详情 | 详情 | |
| (XIV) | 26474 | methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate | C40H53NO14 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)In a further procedure, hydroxy amino ester (VIII) was treated with anisaldehyde dimethyl acetal (XXVII) to provide oxazolidine (XXVIII) as a diastereomeric mixture. Ester hydrolysis of (XXVIII) with LiOH gave acid (XXIX), which was then coupled with taxane (XXX) to furnish ester (XXXI). Acidic treatment of (XXXI) cleaved the oxazolidine and deprotected the silyl ether group to produce (XXXII). Subsequent coupling of (XXXII) with acid (XXVII), followed by reductive deprotection of the trichloroethylcarbonyl group, provided intermediate (XXVI), which was finally converted into the title compound by hydrogenolysis in the presence of p-TsOH as above.
| 【1】 Tsujihari, K.; Hashiyama, T.; Ohashi, M.; Nakanishi, N. (Tanabe Seiyaku Co., Ltd.); Baccatin derivs. and processes for preparing the same. CA 2162759; EP 0712854; JP 1997151181; US 5589502 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 26469 | methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoate | C12H21NO5 | 详情 | 详情 | |
| (XXVI) | 26484 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1,9,12-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (5S,12R)-5-(aminocarbonyl)-12-[(S)-[(tert-butoxycarbonyl)amino](cyclopropyl)methyl]-3,7,10-trioxo-1-phenyl-2,8,11-trioxa-4-azatridecan-13-oate | C54H67N3O20 | 详情 | 详情 | |
| (XXVII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (XXVIII) | 26486 | 3-(tert-butyl) 5-methyl (4S,5R)-4-cyclopropyl-2-(4-methoxyphenyl)-1,3-oxazolidine-3,5-dicarboxylate | C20H27NO6 | 详情 | 详情 | |
| (XXIX) | 26487 | (4S,5R)-3-(tert-butoxycarbonyl)-4-cyclopropyl-2-(4-methoxyphenyl)-1,3-oxazolidine-5-carboxylic acid | C19H25NO6 | 详情 | 详情 | |
| (XXX) | 26488 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-12-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C38H51Cl3O12Si | 详情 | 详情 | |
| (XXXI) | 26489 | 5-[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-12-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl] 3-(tert-butyl) (4S,5R)-4-cyclopropyl-2-(4-methoxyphenyl)-1,3-oxazolidine-3,5-dicarboxylate | C57H74Cl3NO17Si | 详情 | 详情 | |
| (XXXII) | 26490 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoyl]oxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-12-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C43H54Cl3NO16 | 详情 | 详情 | |
| (XXXIII) | 26491 | 2-[((3S)-4-amino-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoyl)oxy]acetic acid | C14H16N2O7 | 详情 | 详情 |