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【结 构 式】 
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【分子编号】19588 【品名】methyl propiolate 【CA登记号】922-67-8 |
【 分 子 式 】C4H4O2 【 分 子 量 】84.07456 【元素组成】C 57.14% H 4.8% O 38.06% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of indoline (I) with propynoic acid methyl ester (II) in methanol gives the acrylic acid derivative (III), which is cyclized by means of Pd(OAc)2 in DMA to yield the pyrroloindole (IV). The reduction of the ester group of (IV) by means of BH3/Me2S in refluxing THF affords intermediate (V), which is treated with CCl4 and PPh3 to provide the chloromethyl derivative (VI). The O-deprotection in (VI) by means of HCOONH4 and Pd/C in THF gives the hydroxy compound (VII), which is N-deprotected by means of HCl in ethyl acetate to yield the pyrroloindole (VIII). The condensation of (VIII) with the known indole carboxylic acid (IX) by means of EDC in DMF affords the carboxamide (X), which is treated with phenyl isocyanate (XI) and TEA in THF to provide the target Carzelesin.
| 【1】 Fukuda, Y.; et al.; Novel syntheses of optically active CC-1065, U-73,975 (adozelesin), U-80,244 (carzelesin), U-77,779 (bizelesin), KW-2189, and DU-86. Heterocycles 1997, 45, 12, 2303. |
| 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) | 59123 | tert-butyl (3S)-3-[(acetyloxy)methyl]-5-amino-6-(benzyloxy)-2,3-dihydro-1H-indole-1-carboxylate | C23H28N2O5 | 详情 | 详情 | |
| (II) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (III) | 59124 | tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate | C27H32N2O7 | 详情 | 详情 | |
| (IV) | 59126 | 6-(tert-butyl) 1-methyl (8S)-8-[(acetyloxy)methyl]-4-(benzyloxy)-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C27H30N2O7 | 详情 | 详情 | |
| (V) | 59127 | tert-butyl (1S)-5-(benzyloxy)-1-(hydroxymethyl)-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate | C24H28N2O4 | 详情 | 详情 | |
| (VI) | 59128 | tert-butyl (1S)-5-(benzyloxy)-1-(chloromethyl)-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate | C24H27ClN2O3 | 详情 | 详情 | |
| (VII) | 59129 | tert-butyl (1S)-1-(chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate | C17H21ClN2O3 | 详情 | 详情 | |
| (VIII) | 59130 | (8S)-8-(chloromethyl)-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indol-4-ol | C12H13ClN2O | 详情 | 详情 | |
| (IX) | 61765 | 5-{[6-(diethylamino)-1-benzofuran-2-yl]carbonyl}-1H-indole-2-carboxylic acid | C22H20N2O4 | 详情 | 详情 | |
| (X) | 61766 | [(1S)-1-(chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5-{[6-(diethylamino)-1-benzofuran-2-yl]carbonyl}-1H-indol-2-yl)methanone | C34H31ClN4O4 | 详情 | 详情 | |
| (XI) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The intermediate pyrroloindole (VIII) was prepared from the previously reported (S)-aminoindoline (I). Michael addition of methyl propiolate (II) to aminoindoline (I) in MeOH provided the aminoacrylate (IIIa-b). Oxidative cyclization of (IIIa-b) was effected with Pd(OAc)2 in DMA to afford the 3-(methoxycarbonyl)pyrroloindole (IV). Simultaneous reduction of both the methyl ester and acetate groups of (IV) with borane-dimethyl sulfide complex gave rise to alcohol (V). Chlorination of (V) to give the chloromethyl derivative (VI) was carried out by treatment with triphenylphosphine and carbon tetrachloride. The O-benzyl protecting group of (VI) was subsequently removed by transfer hydrogenolysis yielding phenol (VII). The N-Boc group of (VII) was then cleaved under acidic conditions to furnish (VIII).
| 【1】 Fukuda, Y.; et al.; Novel syntheses of optically active CC-1065, U-73,975 (adozelesin), U-80,244 (carzelesin), U-77,779 (bizelesin), KW-2189, and DU-86. Heterocycles 1997, 45, 12, 2303. |
| 【2】 Kelly, R.C.; Aristoff, P.A. (Pharmacia Corp.); Novel CC-1065 analogs having two CPI subunits. EP 0359454; JP 1992500664; WO 9002746 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 59124 | tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate | C27H32N2O7 | 详情 | 详情 | |
| (IIIb) | 59125 | tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(Z)-3-methoxy-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate | C27H32N2O7 | 详情 | 详情 | |
| (I) | 59123 | tert-butyl (3S)-3-[(acetyloxy)methyl]-5-amino-6-(benzyloxy)-2,3-dihydro-1H-indole-1-carboxylate | C23H28N2O5 | 详情 | 详情 | |
| (II) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (IV) | 59126 | 6-(tert-butyl) 1-methyl (8S)-8-[(acetyloxy)methyl]-4-(benzyloxy)-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C27H30N2O7 | 详情 | 详情 | |
| (V) | 59127 | tert-butyl (1S)-5-(benzyloxy)-1-(hydroxymethyl)-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate | C24H28N2O4 | 详情 | 详情 | |
| (VI) | 59128 | tert-butyl (1S)-5-(benzyloxy)-1-(chloromethyl)-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate | C24H27ClN2O3 | 详情 | 详情 | |
| (VII) | 59129 | tert-butyl (1S)-1-(chloromethyl)-5-hydroxy-8-methyl-1,6-dihydropyrrolo[3,2-e]indole-3(2H)-carboxylate | C17H21ClN2O3 | 详情 | 详情 | |
| (VIII) | 59130 | (8S)-8-(chloromethyl)-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indol-4-ol | C12H13ClN2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways. Reductive condensation of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride and AcOH provided the benzylcyclohexylamine (II). Further hydrogenolysis of the N-benzyl group of (II) in the presence of Pd/C and oxalic acid yielded cyclohexylamine (III) as the oxalate salt. Sulfonamide (V) was then obtained by condensation with 4-chlorophenylsulfonyl chloride (IV), followed by hydrolysis of the diethyl acetal with aqueous HCl. lternatively, treatment of trans-4-aminocyclohexanol hydrochloride (VI) with sulfonyl chloride (IV) in the presence of Et3N provided the sulfonamide (VII), which was subsequently oxidized with chromic anhydride and H2SO4 to the target ketone (V). Condensation of this intermediate (V) with ethyl formate in the presence of NaH produced the hydroxymethylene cyclohexanone (VIII), which was submitted to a Wittig reaction with phosphorane (IX) to give the cyclohexylidenpropanoic ester (X). Cyclization of this compound using anhydrous p-toluenesulfonic acid in refluxing toluene furnished pyranone (XI), which by subsequent bromination in acetic acid yielded the 3-bromopyranone (XII). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with methyl propiolate (XIII) with concomitant decarboxylation at 200 C. Finally, the ester function of (XIV) was reduced to alcohol (XV) with LiAlH4.
| 【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381. |
| 【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 . |
| 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) | 19576 | 4,4-diethoxycyclohexanone | C10H18O3 | 详情 | 详情 | |
| (II) | 19577 | N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine | C17H27NO2 | 详情 | 详情 | |
| (III) | 19578 | 4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine | C10H21NO2 | 详情 | 详情 | |
| (V) | 19580 | 4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide | C12H14ClNO3S | 详情 | 详情 | |
| (VI) | 19581 | trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (VII) | 19582 | 4-chloro-N-(4-hydroxycyclohexyl)benzenesulfonamide | C12H16ClNO3S | 详情 | 详情 | |
| (VIII) | 19583 | 4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide | C13H14ClNO4S | 详情 | 详情 | |
| (IX) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (X) | 19585 | methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate | C16H18ClNO5S | 详情 | 详情 | |
| (XI) | 19586 | 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide | C15H14ClNO4S | 详情 | 详情 | |
| (XII) | 19587 | N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide | C15H13BrClNO4S | 详情 | 详情 | |
| (XIII) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (XIV) | 19589 | methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylate | C18H17BrClNO4S | 详情 | 详情 | |
| (XV) | 19590 | N-[7-bromo-5-(hydroxymethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide | C17H17BrClNO3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVI)Reaction of L-arabinose (XIII) with cyanamide (XIV) in aqueous methanolic ammonia gives the oxazolidine derivative (XV), which is cyclized with methyl propynoate (XVI) in refluxing ethanol to yield the anhydro uridine (XVII). Acylation of both OH groups of (XVII) by means of benzoyl cyanide (XVIII) in DMF affords the dibenzoate (XIX), which is treated with anhydrous HCl in DMF to provide the chloro uridine derivative (XX) or with HI in DMF or LiI and BH3/Et2O in DMF to provide the iodo uridine (XXI). Dehalogenation of (XX) or (XXI) by means of tri-butyltin hydride in refluxing benzene furnishes 3',5'-di-O-benzoyl-2'-deoxy-b-L-uridine (XXII). The trans-glycosylation of (XXII) with bis(trimethylsilyl)-5-fluorouracil (XXIII) by means of TMS-OTf in acetonitrile gives the corresponding 5-fluoro-L-uridine derivative (XXIV) as a mixture of the a- and b-anomers that is separated by chromatography. Debenzoylation of (XXIV) with ammonia in methanol yields 2'-deoxy-b-L-uridine (XXV), which is treated with MsCl and pyridine to afford the dimesylate (XXVI). Reaction of compound (XXVI) with NaOH in methanol/water provides the unstable intermediate (XXVII) that rearranges to the cyclic ether (XXVIII). Treatment of (XXVIII) with 1,2,4-triazole (XXIX) and p-chlorophenyl dichlorophosphate in pyridine provides the adduct (XXX), which by cleavage of the triazole ring by means of NH4OH in dioxane gives the corresponding cytidine derivative (XXXI). Finally, this compound is treated with potassium tert-butoxide in DMSO.
| 【3】 Gullen, E.; Zhu, Y.-L.; Liu, M.-C.; Dutschman, G.E.; Cheng, Y.-C.; Luo, M.-Z.; Lin, T.-S.; Design and synthesis of 2',3'-dideoxy-2',3'-didehydro-beta-L-cytidine (beta-L-d4C) and 2',3'-dideoxy-2',3'-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human. J Med Chem 1996, 39, 9, 1757. |
| 【1】 Holy, A.; Nucleic acid components and their analogues. CLIII. Preparation of 2'-deoxy-L-ribonucleosides of the pyrimidine series. Coll Czech Chem Commun 1972, 37, 12, 4072. |
| 【2】 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131. |
| 【4】 Lin, T.-S.; Cheng, Y.-C. (Yale University); L-2',3'-Dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents. EP 0707481; JP 1996510747; US 5627160; WO 9427616 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 56917 | alpha-L-arabinofuranose | C5H10O5 | 详情 | 详情 | |
| (XIV) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (XV) | 56918 | (3aS,5S,6S,6aR)-5-(hydroxymethyl)-2-iminohexahydrofuro[2,3-d][1,3]oxazol-6-ol | C6H10N2O4 | 详情 | 详情 | |
| (XVI) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (XVII) | 39999 | (2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-6-one | 3736-77-4 | C9H10N2O5 | 详情 | 详情 |
| (XVIII) | 56919 | 2-oxo-2-phenylacetonitrile | C8H5NO | 详情 | 详情 | |
| (XIX) | 40000 | [(2S,3S,3aR,9aS)-3-(benzoyloxy)-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl]methyl benzoate | C23H18N2O7 | 详情 | 详情 | |
| (XX) | 40001 | [(2S,3S,4S,5S)-3-(benzoyloxy)-4-chloro-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H19ClN2O7 | 详情 | 详情 | |
| (XXI) | 56920 | {(2S,3S,4S,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-iodotetrahydro-2-furanyl}methyl benzoate | C23H19IN2O7 | 详情 | 详情 | |
| (XXII) | 39996 | [(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H20N2O7 | 详情 | 详情 | |
| (XXIII) | 47859 | 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine | 17242-85-2 | C10H19FN2O2Si2 | 详情 | 详情 |
| (XXIV) | 56921 | {(2S,3R,5S)-3-(benzoyloxy)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl benzoate | C23H19FN2O7 | 详情 | 详情 | |
| (XXV) | 54714 | 5-fluoro-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C9H11FN2O5 | 详情 | 详情 | |
| (XXVI) | 54709 | {(2S,3R,5S)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl}methyl methanesulfonate | C11H15FN2O9S2 | 详情 | 详情 | |
| (XXVII) | 54710 | [(1S,9S,10S)-4-fluoro-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0~2,7~]dodeca-3,6-dien-10-yl]methyl methanesulfonate | C10H11FN2O6S | 详情 | 详情 | |
| (XXVIII) | 54711 | 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C9H9FN2O4 | 详情 | 详情 | |
| (XXIX) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XXX) | 54712 | 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-4-(1H-1,2,4-triazol-1-yl)-2(1H)-pyrimidinone | C11H10FN5O3 | 详情 | 详情 | |
| (XXXI) | 54713 | 4-amino-1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2(1H)-pyrimidinone | C9H10FN3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Addition of the lithium acetylide prepared from methyl propiolate (VIII) to 3-ethylpentanal (VII) gives methyl 6-ethyl-4-hydroxy-2-octynoate (IX), which is further oxidized to the corresponding keto ester (X) employing the Jones reagent in acetone. Cycloaddition between alkyne (X) and the lithium derivative of the isobenzofuranone (V) gives rise to the 1,4-epoxy dihydronaphthalene adduct (XI). Subsequent acidic hydrolysis of (XI) furnishes the hydroxy naphthalenone (XII). Finally, reductive aromatization of (XII) using TiCl3 produces the title naphthol compound.
| 【1】 Mori, S.; Takechi, S.; Kida, S. (Shionogi & Co. Ltd.); Process for producing lignan cpd.. EP 0646570; WO 9424087 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 57444 | 3-ethylpentanal | C7H14O | 详情 | 详情 | |
| (VIII) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (IX) | 57445 | methyl 6-ethyl-4-hydroxy-2-octynoate | C11H18O3 | 详情 | 详情 | |
| (X) | 57432 | methyl 6-ethyl-4-oxo-2-octynoate | C11H16O3 | 详情 | 详情 | |
| (XI) | 57443 | 3-(3,4-dimethoxyphenyl)-4,5,6-trimethoxy-2-benzofuran-1(3H)-one | C19H20O7 | 详情 | 详情 | |
| (XII) | 57446 | methyl 8-(3,4-dimethoxyphenyl)-10-(3-ethylpentanoyl)-4,5,6-trimethoxy-1-[(trimethylsilyl)oxy]-11-oxatricyclo[6.2.1.0~2,7~]undeca-2,4,6,9-tetraene-9-carboxylate | C33H44O10Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)Condensation of N-Boc-L-aspartic acid gamma-benzyl ester (I) with N-benzhydryl piperazine (II) using 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBT) as the condensig agents gave amide (III). Reduction of the ester group of (III) with NaBH4 in refluxing EtOH provided alcohol (IV), which was treated with methanesulfonyl chloride to afford mesylate (V). Subsequent reaction of (V) with sodium azide in N,N'-dimethylimidazolidinone gave azide (VI), and further cycloaddition of this azide with methyl propiolate (VII) in refluxing dichloroethane furnished triazole (VIII). The tert-butoxycarbonyl protecting group of (VIII) was then removed by treatment with trifluoroacetic acid at room temperature to yield amine (IX), which was condensed with indole-2-carboxylic acid (X) in the presence of EDC and HOBT to give amide (XI). Finally, hydrolysis of (XI) with LiOH provided the target carboxylic acid.
| 【1】 Ogawa, M.; Morita, T.; Matsuda, K.; Iibuchi, N.; Kidokoro, S. (Tobishi Pharmaceutical Co.); Amino acid deriv. having anti-CKK activity. EP 0710661; JP 1996119940; JP 1996176144; US 5716958 . |
| 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) | 25219 | (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | 7536-58-5 | C16H21NO6 | 详情 | 详情 |
| (II) | 20796 | N-(Benzhydryl)piperazine; 1-Benzhydrylpiperazine; 1-(dibenzyl)piperazine | 841-77-0 | C17H20N2 | 详情 | 详情 |
| (III) | 25220 | benzyl (3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C33H39N3O5 | 详情 | 详情 | |
| (IV) | 25221 | tert-butyl (1S)-1-[(4-benzhydryl-1-piperazinyl)carbonyl]-3-hydroxypropylcarbamate | C26H35N3O4 | 详情 | 详情 | |
| (V) | 25222 | (3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl methanesulfonate | C27H37N3O6S | 详情 | 详情 | |
| (V) | 25223 | tert-butyl (1S)-3-azido-1-[(4-benzhydryl-1-piperazinyl)carbonyl]propylcarbamate | C26H34N6O3 | 详情 | 详情 | |
| (VII) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (VIII) | 25224 | methyl 1-[(3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl]-1H-1,2,3-triazole-5-carboxylate | C30H38N6O5 | 详情 | 详情 | |
| (IX) | 25225 | methyl 1-[(3S)-3-amino-4-(4-benzhydryl-1-piperazinyl)-4-oxobutyl]-1H-1,2,3-triazole-5-carboxylate | C25H30N6O3 | 详情 | 详情 | |
| (X) | 25226 | 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid | 1477-50-5 | C9H7NO2 | 详情 | 详情 |
| (XI) | 25227 | methyl 1-[(3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(1H-indol-2-ylcarbonyl)amino]-4-oxobutyl]-1H-1,2,3-triazole-5-carboxylate | C34H35N7O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Addition of methyl propiolate (I) to 2,4-hexadienal (II) using lithium hexamethyldisilazide afforded diene (III). Subsequent cycloaddition of (III) to 4-phenyl urazole (IV) in the presence of iodobenzene diacetate produced the corresponding triazolopyridazine as a diastereomeric mixture, from which the required cis isomer was isolated by flash chromatography.
| 【1】 McMillan, M.; Cudaback, E.; Misra-Press, A.; et al.; Synthesis and biological studies of a novel inhibitor of NF-kappaB. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 213. |
| 【2】 Eguchi, M.; Qabar, M.N.; Ferguson, M.D.; Babu, S.; Boatman, P.D. Jr.; McMillan, M.K.; Kahn, M.; Ogbu, C.O.; Lum, C.T.; Meara, J.P.; Kim, H.-O.; Urban, J. (Molecumetics Ltd.); Use of beta-sheet mimetics as protease and kinase inhibitors and as inhibitors of transcription factors. US 6117896; WO 9805333 . |
| 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) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (II) | 29433 | (2E,4E)-2,4-hexadienal | 142-83-6 | C6H8O | 详情 | 详情 |
| (III) | 29434 | methyl (5E,7E)-4-hydroxy-5,7-nonadien-2-ynoate | C10H12O3 | 详情 | 详情 | |
| (IV) | 11749 | 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione; 4-Phenyl-1,2,4-triazoline-3,5-dione | 4233-33-4 | C8H5N3O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)11-Azaartemisinin (II) was prepared from artemisinin (I) by reaction with methanolic ammonia, followed by acid treatment. Then, conjugate addition of methyl propiolate (III) to 11-azaartemisinin (II) in the presence of dimethylaminopyridine furnished the title compound.
| 【1】 Katz, E.; et al.; Structure and antimalarial activity of adducts of 11-azaartemisinin with conjugated terminal acetylenes. Bioorg Med Chem Lett 1999, 9, 20, 2969. |
| 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) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 38763 | (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | C15H23NO4 | 详情 | 详情 | |
| (III) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XII)In an alternative procedure, reaction of L-arabinose (X) with cyanamide in the presence of ammonium hydroxide produced the cyclic isourea (XI). Subsequent cycloaddition of methyl propiolate (XII) to (XI) generated the fused pyrimidone system (XIII). After protection of the free hydroxyl groups of (XIII) as the dibenzoate ester (XIV), treatment with HCl in DMF furnished uridine derivative (XV). Dechlorination of (XV) employing Bu3SnH and AIBN afforded intermediate (VIII), which was treated with Lawesson's reagent to give the thiocarbonyl analogue (IX). Finally, sulfur displacement with concomitant benzoate ester hydrolysis employing methanolic ammonia at 100 C in a pressure bomb furnished the title compound.
| 【1】 Bryant, M.L.; Gosselin, G.; Imbach, J.-L. (CNRS (Centre National de la Recherche Scientifique); Novirio Pharmaceuticals Ltd.); beta-L-2'-Deoxy-nucleosides for the treatment of hepatitis B. WO 0009531 . |
| 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) | 39996 | [(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H20N2O7 | 详情 | 详情 | |
| (IX) | 40005 | [(2S,3R,5S)-3-(benzoyloxy)-5-[2-oxo-4-thioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H20N2O6S | 详情 | 详情 | |
| (X) | 39997 | (3R,4R,5S)-5-(hydroxymethyl)tetrahydro-2,3,4-furantriol | C5H10O5 | 详情 | 详情 | |
| (XI) | 39998 | (3aS,5S,6S,6aR)-2-amino-5-(hydroxymethyl)-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]oxazol-6-ol | C6H10N2O4 | 详情 | 详情 | |
| (XII) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (XIII) | 39999 | (2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-6-one | 3736-77-4 | C9H10N2O5 | 详情 | 详情 |
| (XIV) | 40000 | [(2S,3S,3aR,9aS)-3-(benzoyloxy)-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl]methyl benzoate | C23H18N2O7 | 详情 | 详情 | |
| (XV) | 40001 | [(2S,3S,4S,5S)-3-(benzoyloxy)-4-chloro-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H19ClN2O7 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XVI)Cyclization of L-arabinose (VI) with cyanamide and NH3 in methanol gives the bicyclic oxazoline (XV), which is submitted to a cycloaddition with methyl propynoate (XVI) in refluxing ethanol/water to yield the tricyclic pyrimidinone system (XVII). Benzoylation of the two OH groups of compound (XVII) with either benzoyl cyanide and triethylamine in DMF or benzoyl chloride in anhydrous pyridine affords the dibenzoate (XVIII), which is treated with HCl in hot DMF to provide the chlorouridine derivative (XIX). Dechlorination of compound (XIX) by means of Bu3SnH and AIBN in refluxing benzene gives 3,5-di-O-benzoyl-2'deoxy-b-L-uridine (XX), which is debenzoylated by means of NaOMe in methanol to yield 2'-deoxy-b-L- uridine (XXI). Finally, this compound is methylated by reaction with formaldehyde and KOH in hot water followed by hydrogenation with H2 over Pd/C in EtOH/HCl. Optionally, telbivudine can be purified by benzoylation with benzoyl cyanide and TEA, crystallization in EtOH/ether and final hydrolysis with refluxing MeOH/ NaOMe.
| 【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Bayes, M.; Telbivudine. Drugs Fut 2003, 28, 9, 870. |
| 【2】 Holy, A.; Nucleic acid components and their analogues. CLIII. Preparation of 2'-deoxy-L-ribonucleosides of the pyrimidine series. Coll Czech Chem Commun 1972, 37, 12, 4072. |
| 【3】 Bryant, M.L.; Gosselin, G.; Imbach, J.-L. (CNRS (Centre National de la Recherche Scientifique); Novirio Pharmaceuticals Ltd.); beta-L-2'-Deoxy-nucleosides for the treatment of hepatitis B. WO 0009531 . |
| 【4】 Weis, A.L.; Goodhue, C.T.; Shanmuganathan, K. (Genencor International, Inc.); L-Ribofuranosyl nucleosides. WO 9613512 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 62914 | (4R,5S)-5-(hydroxymethyl)tetrahydro-2,4-furandiol | C5H10O4 | 详情 | 详情 | |
| (XV) | 56918 | (3aS,5S,6S,6aR)-5-(hydroxymethyl)-2-iminohexahydrofuro[2,3-d][1,3]oxazol-6-ol | C6H10N2O4 | 详情 | 详情 | |
| (XVI) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (XVII) | 39999 | (2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-6-one | 3736-77-4 | C9H10N2O5 | 详情 | 详情 |
| (XVIII) | 40000 | [(2S,3S,3aR,9aS)-3-(benzoyloxy)-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl]methyl benzoate | C23H18N2O7 | 详情 | 详情 | |
| (XIX) | 40001 | [(2S,3S,4S,5S)-3-(benzoyloxy)-4-chloro-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H19ClN2O7 | 详情 | 详情 | |
| (XX) | 39996 | [(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H20N2O7 | 详情 | 详情 | |
| (XXI) | 11875 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine | 951-78-0 | C9H12N2O5 | 详情 | 详情 |