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【结 构 式】 
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【分子编号】61170 【品名】2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde 【CA登记号】102191-92-4 |
【 分 子 式 】C8H18O2Si 【 分 子 量 】174.31522 【元素组成】C 55.12% H 10.41% O 18.36% Si 16.11% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Enantioselective cycloaddition of dienyne (XVII) with aldehyde (XVIII) affords dihydropyran (XIX). Subsequent Rubottom oxidation of the silyl enol ether (XIX) gives a mixture of epimeric alpha-hydroxy ketones (XX), which is further equilibrated to the desired stereoisomer (XXI) in the presence of K2CO3 in MeOH. After protection of the hydroxyl group of (XXI) as the triisopropylsilyl ether (XXII), Wittig reaction with methylene triphenylphosphorane provides the exocyclic olefin (XXIII). Replacement of the silylated primary hydroxyl of (XXIII) with a iodide group to yield (XXIV) is accomplished by treatment with I2 and PPh3. Removal of the remaining silyl group of (XXIV) with tetrabutylammonium fluoride and acetic acid yields the allylic alcohol (XXV), which can be diastereoselectively epoxidized with t butyl hydroperoxide and vanadyl acetylacetonate, producing (XXVI) as a single isomer. Reprotection of (XXVI) with triisopropylsilyl triflate affords the corresponding silyl ether (XXVII). Hydrozirconation of acetylene (XXVII), followed by Negishi coupling with the vinyl iodide (XVI) furnishes the diene system (XXVIII). Subsequent azido group reduction in (XXVIII) with trimethylphosphine in moist THF provides amine (XXIX).
| 【1】 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 62124 | (2R,3R,5S,6S)-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-yl azide; (2R,3R,5S,6S)-3-azido-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran | C11H18IN3O | 详情 | 详情 | |
| (XVII) | 62125 | triethyl{[(E)-1-methylene-2-penten-4-ynyl]oxy}silane; (E)-1-methylene-2-penten-4-ynyl triethylsilyl ether | C12H20OSi | 详情 | 详情 | |
| (XVIII) | 61170 | 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde | 102191-92-4 | C8H18O2Si | 详情 | 详情 |
| (XIX) | 62126 | tert-butyl(dimethyl)silyl {(2R,6S)-6-ethynyl-4-[(triethylsilyl)oxy]-3,6-dihydro-2H-pyran-2-yl}methyl ether; tert-butyl({(2R,6S)-6-ethynyl-4-[(triethylsilyl)oxy]-3,6-dihydro-2H-pyran-2-yl}methoxy)dimethylsilane | C20H38O3Si2 | 详情 | 详情 | |
| (XX) | 62127 | (2R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-hydroxytetrahydro-4H-pyran-4-one | C14H24O4Si | 详情 | 详情 | |
| (XXI) | 62128 | (2R,3R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-hydroxytetrahydro-4H-pyran-4-one | C14H24O4Si | 详情 | 详情 | |
| (XXII) | 62129 | (2R,3R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-[(triisopropylsilyl)oxy]tetrahydro-4H-pyran-4-one | C23H44O4Si2 | 详情 | 详情 | |
| (XXIII) | 62130 | tert-butyl(dimethyl)silyl {(2R,5S,6R)-6-ethynyl-4-methylene-5-[(triisopropylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl ether; tert-butyl({(2R,5S,6R)-6-ethynyl-4-methylene-5-[(triisopropylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methoxy)dimethylsilane | C24H46O3Si2 | 详情 | 详情 | |
| (XXIV) | 62131 | (2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-yl triisopropylsilyl ether; {[(2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-yl]oxy}(triisopropyl)silane | C18H31IO2Si | 详情 | 详情 | |
| (XXV) | 62132 | (2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-ol | C9H11IO2 | 详情 | 详情 | |
| (XXVI) | 62133 | (3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]octan-4-ol | C9H11IO3 | 详情 | 详情 | |
| (XXVII) | 62134 | (3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl triethylsilyl ether; triethyl{[(3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl]oxy}silane | C15H25IO3Si | 详情 | 详情 | |
| (XXVIII) | 62135 | (3R,4R,5R,7R)-5-{(1E,3E)-5-[(2S,3S,5R,6R)-5-azido-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methyl-1,3-pentadienyl}-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl triethylsilyl ether; {[(3R,4R,5R,7R)-5-{(1E,3E)-5-[(2S,3S,5R,6R)-5-azido-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methyl-1,3-pentadienyl}-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl]oxy}(triethyl)silane | C26H44IN3O4Si | 详情 | 详情 | |
| (XXIX) | 62136 | (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-ylamine | C26H46INO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The intermediate 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XIII) has been obtained as follows: The cyclization of 2-(Tbdms-O)acetaldehyde (IX) with 1-methoxy-3-methylbutadiene (X) by means of a chiral Cr catalyst gives the chiral dihydropyran derivative (XI), which is desilylated and demethoxylated by means of triethylsilane, BF3/Et2O and HCl to yield the dihydropyran methanol derivative (XII). Finally, this compound is oxidized to the target intermediate 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XIII) by means of oxalyl chloride , DMSO and TEA
| 【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 61170 | 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde | 102191-92-4 | C8H18O2Si | 详情 | 详情 |
| (X) | 61171 | (1E)-1-methoxy-3-methyl-1,3-butadiene; methyl (1E)-3-methyl-1,3-butadienyl ether | C6H10O | 详情 | 详情 | |
| (XI) | 61172 | tert-butyl(dimethyl)silyl [(2S,6R)-6-methoxy-4-methyl-3,6-dihydro-2H-pyran-2-yl]methyl ether; tert-butyl{[(2S,6R)-6-methoxy-4-methyl-3,6-dihydro-2H-pyran-2-yl]methoxy}dimethylsilane | C14H28O3Si | 详情 | 详情 | |
| (XII) | 61173 | [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methanol | C7H12O2 | 详情 | 详情 | |
| (XIII) | 61148 | (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde | C7H10O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The cyclization of 1-(2-fluorobenzyl)pyrazolo[3,4-b]pyridine-3-carboxamidine (I) (see scheme no. 28591301a, intermediate (IX)) with phenylazomalononitrile (II) by means of NaOMe in hot DMF gives the pyrimidine (III), which is reduced with H2 over RaNi in hot DMF to yield the triaminopyrimidine (IV). The reductocondensation of (IV) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (V) by means of NaBH3CN in methanol/AcOH affords the adduct (VI), which is desilylated by means of TBAF in THF to provide the 2-hydroxyethylamino derivative (VII). Finally, this compound is cyclized with aqueous glyoxal (VIII) to furnish the target tricyclic compound.
| 【1】 Straub, A.; Benet-Buckholz, J.; Fröde, R.; Kern, A.; Kohlsdorfer, C.; Schmitt, P.; Schwarz, T.; Siefert, H.-M.; Stasch, J.-P.; Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase. Bioorg Med Chem 2002, 10, 6, 1711. |
| 【2】 Kern, A.; Stasch, J.-P.; Straub, A.; Dembowsky, K.; Alonso-Alija, C. (Bayer AG); Substd. pyrazole deriv.. DE 10021069; WO 0183490 . |
| 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) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
| (II) | 63162 | 2-[(E)-2-phenyldiazenyl]malononitrile | 6017-21-6 | C9H6N4 | 详情 | 详情 |
| (III) | 63163 | 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine | 428854-23-3 | C23H18FN9 | 详情 | 详情 |
| (IV) | 63164 | 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylamine; 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine | 428854-24-4 | C17H15FN8 | 详情 | 详情 |
| (V) | 61170 | 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde | 102191-92-4 | C8H18O2Si | 详情 | 详情 |
| (VI) | 63165 | N~5~-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine; 6-amino-5-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinylamine | C25H33FN8OSi | 详情 | 详情 | |
| (VII) | 63166 | 2-({4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl}amino)-1-ethanol | C19H19FN8O | 详情 | 详情 | |
| (VIII) | 32557 | glyoxal; 2-oxoacetaldehyde | 107-22-2 | C2H2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Selective N-protection of sisomicin (I) with HONB-pNz (prepared in situ by reaction of N-hydroxy-5-norbornene-2,3-dicarboximide [HONB] with p-nitrobenzylchloroformate [pNzCl] and Et3N in THF) by means of zn(OAc)2 in MeOH/CH2Cl2 gives 6’-pNz-sisomicin (II), which is selectively protected at the glycosidyl amino groups with HONB-Boc (prepared by reacting HONB with Boc2O and Et3N in THF) by means of zn(OAc)2 and Et3N in MeOH/THF to yield 6’-pNz-2’,3-diBoc-sisomicin (III). Protection of the remaining amino groups of compound (III) with HONB-Fmoc (prepared by reacting HONB with Fmoc-Cl by means of NMM in THF) and Boc2O in the presence of NMM in THF provides 6’-pNz-2’,3,3’’-triBoc-1-Fmoc-sisomicin (IV), which is selectively deprotected by removing the Fmoc-group by means of N(CH2CH2NH2)3 in CH2Cl2 to afford 6’-pNz-2’,3,3’’-triBoc-sisomicin (V). Condensation of protected sisomicin (V) with N-Boc-4- amino-2(S)-hydroxybutyric acid (VI) [prepared by N-protection of 4-amino-2(S)-hydroxybutyric acid (VII) with Boc2O and K2CO3 in diox-ane/H2O] in the presence of HONB and EDC in DMF generates 6’-pNz-2’,3,3’’-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutyryl)sisomicin (VIII). Basic hydrolysis of the 6’-pNz group of compound (VIII) by means of NaOH and Na2S2O4 in EtOH/H2O at 70 °C results in 2’,3,3’’-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutryl)sisomicin (IX), which then undergoes reductive alkylation with tert-butyldimethylsilyloxy acetaldehyde (X) in the presence of silica-supported cyanoboro -hydride (Si-CBH) in MeOH at 100 °C (microwave) to give the 6’-[2-(tert-butyldimethylsilyl oxy)ethyl]sisomicin derivative (XI). Finally, compound (IX) is completely deprotected by means of TFA in CH2Cl2 .
| 【1】 Aggen, J., Goldblum, A.A., linsell, M., Dozzo, P., Moser, H.E., Hildebrandt, D., Gliedt, M. (Achaogen, Inc.). Antibacterial aminoglycoside analogs. CN 101868472, CN 103360440, EP 2217610, JP 2011504508, JP 2011219498, KR 2010110297, US 8383596, US 2013217642, WO 2009067692. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 67690 | 4-nitrobenzyl (((2R,3S)-3-amino-2-(((1S,3R,4S,6R)-4,6-diamino-3-(((2S,3S,4S,5S)-3,5-dihydroxy-5-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexyl)oxy)-3,4-dihydro-2H-pyran-6-yl)methyl)carbamate | C27H42N6O11 | 详情 | 详情 | |
| (I) | 44199 | (2R,3R,4R,5R)-2-[((1S,2R,3R,4S,6R)-4,6-diamino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-5-methyl-4-(methylamino)tetrahydro-2H-pyran-3,5-diol; Sisomicin | 32385-11-8 | C19H37N5O7 | 详情 | 详情 |
| (III) | 67691 | C37H58N6O15 | 详情 | 详情 | ||
| (IV) | 67692 | C57H76N6O19 | 详情 | 详情 | ||
| (V) | 67693 | C42H66N6O17 | 详情 | 详情 | ||
| (VI) | 67688 | N-Boc-4-amino-2(S)-hydroxybutyric acid | 207305-60-0 | C9H17NO5 | 详情 | 详情 |
| (VII) | 67689 | 4-amino-2(S)-hydroxybutyric acid | 7013-05-0 | C4H9NO3 | 详情 | 详情 |
| (VIII) | 67694 | 6'-pNz-2’,3,3''-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutyryl)sisomicin | C51H81N7O21 | 详情 | 详情 | |
| (IX) | 67695 | 2',3,3''-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutryl)sisomicin | C43H76N6O17 | 详情 | 详情 | |
| (X) | 61170 | 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde | 102191-92-4 | C8H18O2Si | 详情 | 详情 |
| (XI) | 67696 | 6'-[2-(tert-butyldimethylsilyl oxy)ethyl]sisomicin | C51H94N6O18Si | 详情 | 详情 |