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【结 构 式】 
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【分子编号】14346 【品名】di(tert-butyl) malonate; Di-tert-butyl malonate 【CA登记号】541-16-2 |
【 分 子 式 】C11H20O4 【 分 子 量 】216.2774 【元素组成】C 61.09% H 9.32% O 29.59% |
合成路线1
该中间体在本合成路线中的序号：Several partial syntheses of docetaxel have been described: The selective hydrolysis of Taxol A (I, R = Ph), Taxol B (I, R = C(Me)=CHMe) or Taxol C (I, R = C5H11) with NaHCO3 in THF/water gives the corresponding 10-deacetyl derivatives (II), which by selective silylation with triethylsilyl chloride in pyridine are converted into the 10-deacetyl-2',7-bis(triethylsilyl) compounds (III). The reaction of compounds (III) with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in THF afford the corresponding imino derivatives (IV), which, without isolation are hydrolyzed and desilylated by a treatment with concentrated aqueous HCl in ethanol giving 10-deacetyltaxolamine (V). Finally, this compound is acylated at the amino group by a treatment by di-tert-butyl dicarbonate and NaHCO3 in ethyl acetate/water.
| 【1】 Young, T.H. (Hauser, Inc.); Preparation of Taxol and docetaxel through primary amines. EP 0852581; WO 9623780 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14346 | di(tert-butyl) malonate; Di-tert-butyl malonate | 541-16-2 | C11H20O4 | 详情 | 详情 | |
| (IIa) | 10470 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-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-2-yl benzoate | C45H49NO13 | 详情 | 详情 | |
| (Ia) | 10595 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 33069-62-4 | C47H51NO14 | 详情 | 详情 |
| (Ib) | 10731 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9-dihydroxy-15-[((2R,3S)-2-hydroxy-3-[[(E)-2-methyl-2-butenoyl]amino]-3-phenylpropanoyl)oxy]-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C45H53NO14 | 详情 | 详情 | |
| (IIIa) | 12495 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C57H77NO13Si2 | 详情 | 详情 | |
| (IVa) | 12496 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-11-oxo-15-([(2R,3S)-3-phenyl-3-[[(E)-benzylidene]amino]-2-[(triethylsilyl)oxy]propanoyl]oxy)-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C57H77NO12Si2 | 详情 | 详情 | |
| (Ic) | 28490 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(cyclopentylcarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C46H55NO14 | 详情 | 详情 | |
| (IIb) | 28491 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12-trihydroxy-15-[((2R,3S)-2-hydroxy-3-[[(Z)-2-methyl-2-butenoyl]amino]-3-phenylpropanoyl)oxy]-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C43H51NO13 | 详情 | 详情 | |
| (IIc) | 28492 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(cyclopentylcarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy)-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-2-yl benzoate | C44H53NO13 | 详情 | 详情 | |
| (IIIb) | 28493 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-15-([(2R,3S)-3-[[(Z)-2-methyl-2-butenoyl]amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C55H79NO13Si2 | 详情 | 详情 | |
| (IIIc) | 28494 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(cyclopentylcarbonyl)amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C56H81NO13Si2 | 详情 | 详情 | |
| (IVb) | 28495 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-15-([(2R,3S)-3-[[(E,2Z)-2-methyl-2-butenylidene]amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C55H79NO12Si2 | 详情 | 详情 | |
| (IVc) | 28496 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[[(E)-cyclopentylmethylidene]amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C56H81NO12Si2 | 详情 | 详情 | |
| (V) | 12497 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-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-2-yl benzoate | C38H45NO12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)A new synthesis for T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with SOCl2 and ethanol gives ethyl 2,3,4,5-tetrafluorobenzoate (II), which is condensed with di-tert-butyl malonate (III) by means of NaH in DMF and decarboxylated with HCl/trifluoroacetic acid to 4-(carboxymethyl)-2,3,5-trifluorobenzoic acid ethyl ester (IV). Esterification of (IV) with diphenyldiazomethane in ether affords the corresponding ester (V), which is methylenated with bis(dimethylamino)methane (VI) and acetic anhydride in DMSO to give 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoic acid ethyl ester (VII). The cyclopropanation of (VII) with trimethylsulfoxonium iodide and potassium tert-butoxide [(CH3)2SO=CH2] yields the cyclopropane compound (VIII), which is selectively hydrolyzed with trifluoroacetic acid to 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoic acid ethyl ester (IX). The decarboxylative amination of (IX) with ethyl chloroformate, sodium azide and benzyl alcohol gives 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid ethyl ester (X), which is saponified with NaOH in dioxane/ethanol to the corresponding acid (XI). The condensation of (XI) with the magnesium salt of malonic acid mono-tert-butyl ester (XII) by means of carbonyldiimidazole (Im2CO) in THF affords the benzoylacetic ester (XIII), which is treated first with dimethylformamide dimethylacetal (XIV) in refluxing benzene and then with 2-amino-1-propanol (XV) to yield 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)-2-propenoic acid ethyl ester (XVI). The cyclization of (XVI) by means of K2CO3 in hot DMF gives the pyridobenzoxazine (XVII), which is saponified with NaOH in ethanol/dioxane to the corresponding free acid (XVIII). Finally, the amino group of (XVIII) is deprotected by hydrogenation with H2 over Pd/C
| 【1】 Fukuoka, Y.; Nitta, J.; Todo, Y.; Nishida, N.; Saikawa, I.; Narita, H.; Miyajima, M.; Yamashiro, Y.; Pyridonecarboxylic acids as antibacterial agents. VIII. Synthesis and structure-activity relationship of 7-(1-aminocyclopropyl)-4-oxo-1,8-naphthyridine-3-carboxylic acids and 7-(1-aminocyclopropyl)-4-oxoquinoline-3-carboxylic acids. Chem Pharm Bull 1994, 42, 10, 2063. |
| 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) | 14328 | 2,3,4,5-tetrafluorobenzoic acid | 1201-31-6 | C7H2F4O2 | 详情 | 详情 |
| (II) | 14313 | diethyl (2S)-2-[(4-[2-[(6R)-2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate | C27H35N5O7 | 详情 | 详情 | |
| (III) | 14346 | di(tert-butyl) malonate; Di-tert-butyl malonate | 541-16-2 | C11H20O4 | 详情 | 详情 |
| (IV) | 14315 | 2-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]acetic acid | C11H9F3O4 | 详情 | 详情 | |
| (V) | 14316 | ethyl 4-[2-(benzhydryloxy)-2-oxoethyl]-2,3,5-trifluorobenzoate | C24H19F3O4 | 详情 | 详情 | |
| (VI) | 14349 | N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine | 51-80-9 | C5H14N2 | 详情 | 详情 |
| (VII) | 14318 | ethyl 4-[1-[(benzhydryloxy)carbonyl]vinyl]-2,3,5-trifluorobenzoate | C25H19F3O4 | 详情 | 详情 | |
| (VIII) | 14319 | ethyl 4-[1-[(benzhydryloxy)carbonyl]cyclopropyl]-2,3,5-trifluorobenzoate | C26H21F3O4 | 详情 | 详情 | |
| (IX) | 14320 | 1-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]cyclopropanecarboxylic acid | C13H11F3O4 | 详情 | 详情 | |
| (X) | 14353 | benzyl N-[1-(4-acetyl-2,3,6-trifluorophenyl)cyclopropyl]carbamate | C19H16F3NO3 | 详情 | 详情 | |
| (XI) | 14322 | 4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoic acid | C18H14F3NO4 | 详情 | 详情 | |
| (XII) | 14355 | Bis(malonic acid monoethyl ester) magnesium salt | C10H14MgO8 | 详情 | 详情 | |
| (XIII) | 14323 | ethyl 3-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorophenyl]-3-oxopropanoate | C22H20F3NO5 | 详情 | 详情 | |
| (XIV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XV) | 14358 | 2-amino-1-propanol; DL-Alaninol | 6168-72-5 | C3H9NO | 详情 | 详情 |
| (XVI) | 14359 | ethyl (E)-2-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoyl]-3-[(2-hydroxy-1-methylethyl)amino]-2-propenoate | C26H27F3N2O6 | 详情 | 详情 | |
| (XVII) | 14360 | ethyl 10-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C26H25FN2O6 | 详情 | 详情 | |
| (XVIII) | 14361 | 10-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid | C24H21FN2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of di-tert-butyl malonate (I) with ethyl 2-bromoacetate (II) by means of NaH in THF gives di-tert-butyl 2-(ethoxycarbonylmethyl)malonate (III), which is condensed with trans-4-methylcyclohexylcarbonyl chloride (IV) by means of NaH in THF, and without isolation is treated with p-toluenesulfonic acid in refluxing toluene to afford trans-4-(4-methylcyclohexyl)-4-oxobutyric acid ethyl ester (V). Finally, this compound is hydrolyzed with aqueous NaOH.
| 【1】 Shinkai, H.; Ozeki, H.; Motomura, T.; Ohta, T.; Furukawa, N.; Uchida, I.; 4-(trans-4-Methylcyclohexyl)-4-oxobutyric acid (JTT-608). A new class of antidiabetic agent. J Med Chem 1998, 41, 27, 5420. |
| 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) | 14346 | di(tert-butyl) malonate; Di-tert-butyl malonate | 541-16-2 | C11H20O4 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 24798 | 1,1-di(tert-butyl) 2-ethyl 1,1,2-ethanetricarboxylate | C15H26O6 | 详情 | 详情 | |
| (IV) | 24799 | 4-methylcyclohexanecarbonyl chloride | C8H13ClO | 详情 | 详情 | |
| (V) | 24800 | ethyl 4-(4-methylcyclohexyl)-4-oxobutanoate | C13H22O3 | 详情 | 详情 |