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【结 构 式】 
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【分子编号】19319 【品名】N-benzyl-N-[2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinyl]amine; N-benzyl-2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinamine 【CA登记号】 |
【 分 子 式 】C17H16Cl2N6 【 分 子 量 】375.25988 【元素组成】C 54.41% H 4.3% Cl 18.9% N 22.4% |
合成路线1
该中间体在本合成路线中的序号：(XV)Aldol condensation between (S)-2-(benzyloxy)-3-methylbutanal (XI) and thioacetal (XII) by means of LDA, tert-butyldimethylsilyl chloride and tin tetrachloride in THF/HMPA gives syn diastereomer (XIII), which is then reduced with LiAlH4 in ether to provide diol (XIV). Protection of the primary hydroxyl group of (XIV) with tert-butyldimethylsilyl chloride in the presence of DMAP and Et3N, followed by reaction with chloride (XV) and DIEA in CH2Cl2, affords protected derivative (XVI), whose benzyl group is then removed by treatment with Na/NH3. The resulting alcohol (XVII) is acetylated with acetic anhydride in CH2Cl2 in the presence of DMAP to give acetate (XVIII). Treatment of D-alloisoleucine (XX) with N-[[(benzyloxy)carbonyl]oxy]-5-norbornene-2,3-dicarboximide and Et3N in THF/H2O, followed by reaction with 1,1'-carbonyldiimidazole (CDI), provides the corresponding imidazolide (XIX), which is then condensed with derivative (XVIII) to yield beta-keto ester (XXI). Reduction of (XXI) with KBH4 in EtOH, followed by protection with triiospropylsilyl triflate, affords a mixture of two diastereomers from which compound (XXII) is cromatographically isolated. Removal of the carbobenzyloxy group of (XXII) by hydrogenation over Pd/C gives amino derivative (XXIII), which is then coupled to intermediate (VIII) by means of isopropenyl chloroformate and NMM in THF to furnish linear peptide (XXIV).
| 【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 50759 | 4-[[(benzyloxy)carbonyl]oxy]-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C17H15NO5 | 详情 | 详情 | ||
| (VIII) | 50750 | (2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butyric acid | C39H54N4O11 | 详情 | 详情 | |
| (XI) | 50751 | (2S)-2-(benzyloxy)-3-methylbutanal | C12H16O2 | 详情 | 详情 | |
| (XII) | 50752 | tert-butyl(dimethyl)silyl (E)-1-(tert-butylsulfanyl)-1-propenyl ether; tert-butyl[[(E)-1-(tert-butylsulfanyl)-1-propenyl]oxy]dimethylsilane | C13H28OSSi | 详情 | 详情 | |
| (XIII) | 50753 | S-(tert-butyl) (2S,3S,4S)-4-(benzyloxy)-3-hydroxy-2,5-dimethylhexanethioate | C19H30O3S | 详情 | 详情 | |
| (XIV) | 50754 | (2R,3S,4S)-4-(benzyloxy)-2,5-dimethyl-1,3-hexanediol | C15H24O3 | 详情 | 详情 | |
| (XV) | 19319 | N-benzyl-N-[2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinyl]amine; N-benzyl-2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinamine | C17H16Cl2N6 | 详情 | 详情 | |
| (XVI) | 50755 | (5S,6R)-5-[(1S)-1-(benzyloxy)-2-methylpropyl]-6,9,9,10,10-pentamethyl-2,4,8-trioxa-9-silaundecane; benzyl (1S,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl ether | C23H42O4Si | 详情 | 详情 | |
| (XVII) | 50756 | (3S,4S,5R)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-(methoxymethoxy)-2,5-dimethyl-3-hexanol | C16H36O4Si | 详情 | 详情 | |
| (XVIII) | 50757 | (1S,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl acetate | C18H38O5Si | 详情 | 详情 | |
| (XIX) | 50758 | benzyl (1R,2S)-1-(1H-imidazol-1-ylcarbonyl)-2-methylbutylcarbamate | C17H21N3O3 | 详情 | 详情 | |
| (XX) | 21073 | (2R,3S)-2-amino-3-methylpentanoic acid | C6H13NO2 | 详情 | 详情 | |
| (XXI) | 50760 | (1S,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl (4R,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate | C32H55NO8Si | 详情 | 详情 | |
| (XXII) | 50761 | (1S,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl (3S,4R,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate | C41H77NO8Si2 | 详情 | 详情 | |
| (XXIII) | 50762 | (1S,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl (3S,4R,5S)-4-amino-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate | C33H71NO6Si2 | 详情 | 详情 | |
| (XXIV) | 50763 | (1S,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl (3S,4R,5S)-4-([(2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butanoyl]amino)-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate | C72H123N5O16Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The cyclization of ethyl cyanoacetate (I) with urea (II) in ethanolic NaOEt provided 6-aminouracil (III). Nitrosation of (III) with NaNO2 in aqueous AcOH, followed by reduction of the resulting nitroso compound (IV) using sodium hydrosulfite gave 5,6-diaminouracil, which was purified by conversion to its hydrochloride salt (V). Condensation of this diamine with melted oxalic acid produced tetrahydroxypteridine (VI). Subsequent reaction of (VI) with PCl5 and POCl3 afforded tetrachlorocompound (VII). The reaction of (VII) with pyrrolidine (VIII) in aqueous KHCO3/CHCl3 resulted in a mixture of 2-, 4-, 7- and 4,7-substituted compounds, from which the desired 4-pyrrolidino-2,6,7-trichloropteridine (IX) was isolated by column chromatography. Further treatment of (IX) with benzylamine (X) in dioxan at r.t. provided diamine (XI). Finally, substitution of the third chlorine atom for piperazine (XII) was accomplished in boiling dioxan.
| 【1】 Merz, K.-H.; Marko, D.; Regiert, T.; Reiss, G.; Frank, W.; Eisenbrand, G.; Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth. J Med Chem 1998, 41, 24, 4733. |
| 【2】 Taylor, E.C. Jr.; Sherman, W.R.; Diaminouracil hydrochloride. Org Synth Coll 1957, 37, 15. |
| 【3】 Schopf, C.; Reichert, R.; Zur kenntnis des leukopterins. Liebigs Ann Chem 1941, 548, 82. |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (III) | 19311 | 6-amino-2,4(1H,3H)-pyrimidinedione | 873-83-6 | C4H5N3O2 | 详情 | 详情 |
| (IV) | 19312 | 6-amino-5-nitroso-2,4(1H,3H)-pyrimidinedione | C4H4N4O3 | 详情 | 详情 | |
| (V) | 19313 | 5,6-diamino-2,4(1H,3H)-pyrimidinedione | 3240-72-0 | C4H6N4O2 | 详情 | 详情 |
| (VI) | 19314 | 2,4,6,7-pteridinetetrol | C6H4N4O4 | 详情 | 详情 | |
| (VII) | 19315 | 2,4,6,7-tetrachloropteridine | C6Cl4N4 | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 19317 | 2,6,7-trichloro-4-(1-pyrrolidinyl)pteridine | C10H8Cl3N5 | 详情 | 详情 | |
| (X) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XI) | 19319 | N-benzyl-N-[2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinyl]amine; N-benzyl-2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinamine | C17H16Cl2N6 | 详情 | 详情 | |
| (XII) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |