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[ CAS No. 75747-14-7 ] {[proInfo.proName]}

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Wnuk, Maciej ; Del Sol-Fernández, Susel ; B?oniarz, Dominika , et al. DOI: PubMed ID:

Abstract: The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@ CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

Keywords: iron oxide nanoparticles ; CD26 ; HSP90 inhibitor ; drug-induced senescence ; skin cells ; senolysis

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Product Details of [ 75747-14-7 ]

CAS No. :75747-14-7 MDL No. :MFCD04973892
Formula : C31H43N3O8 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 585.69 Pubchem ID :-
Synonyms :
17-AAG;NSC 330507;17-AAG, 17 AAG, 17AAG, BAY 57-9352, BAY 579352, BAY579352, KOS-953, KOS-953, KOS-953, Tanespimycin;BMS 722782;KOS 953;CP 127374
Chemical Name :(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(Allylamino)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate

Safety of [ 75747-14-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 75747-14-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 75747-14-7 ]

[ 75747-14-7 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 503-29-7 ]
  • [ 1189-71-5 ]
  • [ 75747-14-7 ]
  • 17-(allylamino)-11-<(azetidinylsulfamyl)carbonyl>geldanamycin [ No CAS ]
  • 2
  • [ 1189-71-5 ]
  • [ 75-31-0 ]
  • [ 75747-14-7 ]
  • 17-(allylamino)-11-<(isopropylsulfamyl)carbonyl>geldanamycin [ No CAS ]
  • 3
  • [ 75747-14-7 ]
  • Carbamic acid (4E,6Z,10E)-(8S,9S,12S,13S,14S,16R)-19-allylamino-13-fluoro-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-aza-bicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl ester [ No CAS ]
  • 5
  • [ 107-11-9 ]
  • [ 30562-34-6 ]
  • [ 75747-14-7 ]
YieldReaction ConditionsOperation in experiment
99% In chloroform; at 20℃; for 18h; (+) -Geldanamycin (5.1 mg, 9. 0 mol) was stirred with allylamine (10.0 ul, 0.13 mmol) in chloroform (1.5 ml) at room temperature. Upon the complete conversion of GA shown by thin layer chromatography (18 hours), the mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Separation by flash column chromatography on silica gel (hexane/ethyl acetate) gave the product as a purple solid (5.3 mg, 99%). IR (KBr) (can~') 3464,3333, 2958,2929, 2825,1728, 1691,1652, 1571,1485, 1372,1323, 1189,1101, 1057; UV (95% EtOH) (nm) 332 (s = 2. 0 x 104) ;'H NMR (CDC13, 500 MHz) 8 9. 14 (s, 1H), 7.28 (s, 1H), 6.93 (bd, J= 11.5 Hz, 1H), 6.56 (bdd, J= 11. 5,11. 0 Hz, 1H), 6.38 (bt, J= 6. 0 Hz, 1H), 5.94-5. 81 (m, 3H), 5.30-5. 24 (m, 2H), 5.17 (s, 1H), 4.82 (bs, 2H), 4.29 (bd, J= 10.0 Hz, 1H), 4.21 (bs, 1H), 4.18-4. 08 (m, 2H), 3.55 (ddd, J= 9.0, 6.5, 2.0 Hz, 1H), 3.43 (ddd, J= 9.0, 3.0, 3.0 Hz, 1H), 3. 34 (s, 3H), 3.25 (s, 3H), 2.72 (dqd, J= 9.5, 7.0, 2.0 Hz, 1H), 2.63 (d, J= 14.0 Hz, 1H), 2.34 (dd, J= 14. 0,11. 0 Hz, 1H), 2.00 (bs, 3H), 1.78 (d, J= 1.0 Hz, 3H), 1.78-1. 74 (m, 2H), 1.74-1. 67 (m, 1H), 0.99-0. 95 (m, 6H) ; 3C NMR (CDC13, 125 MHz, assignment of protonated carbons aided by DEPT) 8 183.8 (18-C), 180.9 (21-C), 168.4 (1-C), 156.0 (7- OzCNHz), 144.6 (17-C), 141.2 (20-C), 135.8 (5-C), 134.9 (2-C), 133.7 (9-C), 132.7 (8-C), 132.5 (3'-C), 126.9 (4-C), 126.5 (3-C), 118.5 (3'-C), 108.8 (19-C), 108.7 (16-C), 81.6 (7-C), 81.4 (12-C), 81.2 (6-C), 72.6 (11-C), 57.1 (6-or 12-OCH3), 56.7 (6-or 12-OCH3), 47.8 (1'-C), 35.0 (13-C), 34.3 (15-C), 32.3 (10-C), 28.4 (14-C), 22.9 (14-CH3), 12.8 (8-CH3), 12.6 (2-CH3), 12.3 (10-CH3); HRMS (FAB) found 586.3120 [M+H] +, calcd. 586.3129 for C31H44N30g.
95% In dichloromethane; at 23℃; 17-AAG was synthesized in the lab from geldanamycin (GA) (LC Laboratories, Woburn, MA). Briefly, 100 mg of GA (0.2 mmol) was dissolved in 2 mL of dry CH2Cl2. Next, 5 equivalents of allylamine (57.1 g/mol, d = 0.763 g/mL) was added dropwise to the flask. The reaction was stirred at room temperature (RT; ?23 C) under low light until complete by TLC analysis (approx. 2 days) (95:5 CHCl3:MeOH, Rf 0.21), precipitated with hexane (3x), centrifuged at 2000 g's for 15 minutes, and evaporated to dryness. Yield: 95 mg, 95%; MS m/z 584 (M-); 1H NMR (CDCl3) delta 0.99 (m, 6H, 10-Me, 14-Me), 1.25 (t, 1H, H-13), 1.60-1.85 (br m, 6H, H-13, H-14, 8-Me), 2.05 (s, 3H, 2-Me), 2.46 (br m, 2H, H-15), 2.83-2.90 (br m, 3H, H-10), 3.27 (s, 3H, OMe), 3.36 (s, 3H, OMe), 3.40 (t, 1H, H-12), 3.58-3.68 (br m, 2H, H-11, H-23), 4.31 (d, 1H, H-7), 5.10 (br s, 1H), 5.21-5.55 (br m, 3H, H-9, H-24), 5.86-5.99 (br t, 2H, H-5, H-23), 6.59 (t, 1H, H-4), 6.94 (d, 1H, H-3), 7.28 (br s, 1H, H-19).
82.6% In tetrahydrofuran; at 20℃; for 4h; To 45.0 g (80.4 mmol) of geldanamycin in 1.45 L of dry THF in a dry 2 L flask was added drop-wise over 30 minutes 36.0 mL (470 mmol) of allyl amine in 50 mL of dry THF. The reaction mixture was stirred at room temperature under nitrogen for 4 hr at which time TLC analysis indicated the reaction was complete [(GDM: bright yellow: Rf=0.40; (5% MeOH-95% CHCl3); 17-AAG: purple: Rf=0.42 (5% MeOH-95% CHCl3)]. The solvent was removed by rotary evaporation and the crude material was slurried in 420 mL of H2O:EtOH (90:10) at 25 C., filtered and dried at 45 C. for 8 hr to give 40.9 g (66.4 mmol) of 17-AAG as purple crystals (82.6% yield, >98% pure by HPLC monitored at 254 nm). MP 206-212 C. 1H NMR and HPLC are consistent with the desired product.
82.6% In tetrahydrofuran; at 20℃; for 4.5h; To 45.0 g (80.4 mmol) of geldanamycin in 1.45 L of dry THF in a dry 2 L flask was added drop-wise over 30 minutes 36.0 mL (470 mmol) of allyl amine in 50 mL of dry THF. The reaction mixture was stirred at room temperature under nitrogen for 4 hr at which time TLC analysis indicated the reaction was complete [(GDM: bright yellow: Rf=0.40; (5% MeOH-95% CHCl3); 17-AAG: purple: Rf=0.42 (5% MeOH-95% CHCl3)]. The solvent was removed by rotary evaporation and the crude material was slurried in 420 mL of H2O:EtOH (90:10) at 25 C., filtered and dried at 45 C. for 8 hr to give 40.9 g (66.4 mmol) of 17-AAG as purple crystals (82.6% yield, >98% pure by HPLC monitored at 254 nm). m.p. 206-212 C. 1H NMR and HPLC are consistent with the desired product.
82.6% In tetrahydrofuran; at 20℃; for 4.5h; To 45.0 g (80.4 mmol) of geldanamycin in 1.45 L of dry THF in a dry 2 L flask was added drop-wise over 30 minutes, 36.0 mL (470 mmol) of allyl amine in 50 mL of dry THF. The reaction mixture was stirred at room temperature under nitrogen for 4 hr at which time TLC analysis indicated the reaction was complete [(GDM: bright yellow: Rf=0.40; (5% MeOH-95%CHCl3); 17-AAG: purple: Rf=0.42 (5% MeOH-95% CHCl3)]. The solvent was removed by rotary evaporation and the crude material was slurried in 420 mL of H2O:EtOH (90:10) at 25 C., filtered and dried at 45 C. for 8 hr to give 40.9 g (66.4 mmol) of 17 purple crystals (82.6% yield, >98% pure by HPLC monitored at 254 nm). MP 206-212 C. as determined using differential scanning colorimetry (DSC). 1H NMR and HPLC are consistent with the desired product.
77% In dichloromethane; at 20℃; for 6h; To a solution of geldanamycin (20.0 g, 35.7 mmol, 1 eq.) in DCM (750 mL) was added allylamine (53 mL, 714 mmol, 20 eq) at room temperature and under nitrogen atmosphere. The slurry was stirred at room temperature for 6 hours. The resulting purple solution was quenched with water (300 mL) and acidified with 2N HCl (300 mL) to pH 3 and stirred for and additional 30 min. The aqueous phase was extracted with DCM (300 mL) and the combined organic layers washed with water (300 mL), dried over MgSO4, filtered, and concentrated. The purple residue was dissolved into acetone (300 mL) at 60 C. and heptanes (1.5 L) was added and the resulting mixture cooled to 5 C., filtered, and the solid washed with heptane (200 mL) to afford crude 17-AAG (18.15 g) after drying. The purple solid was dissolved in of acetone (306 mL) heated to 55-60 C. and n-heptane (1.2 L) was slowly added to form a slurry. The mixture was maintained at 55 C. for 30 minutes and cooled to room temperature. The crystalline material was collected and dried under vacuum for 48 hours to afford 17-AAG as purple needles. (16.15 g, 28 mmol, 77% yield). >99% pure by HPLC monitoreda254 nm) mp 210-212 C.
In MeTHF; at 40℃; for 10h; Geldanamycin (28) (0.14 g, 0.25 mmol, 1.0 equiv) add to a 10 mL vial followed by a solution of allyl amine (0.075 mL, 1.0 mmol, 4 equiv. ) in MeTHF (0.625 mL). The resulting slurry is heated to 40 C under nitrogen for 10 hours. The reaction mixture was then cooled to room temperature, diluted with 1.0 mL of MeTHF, washed with a saturated NH4C1 solution (1.5 mL) and saturated NaCl (1.5 mL). The organic layer was then collected and treated with a freshly prepared aqueous solution of sodium hydrosulfite (1 mL, 20% (m/m) ) with vigorous stirring under nitrogen for 45 minutes. The aqueous layer was then removed and the organic layer was then washed with 1.5 mL of degassed water. The organic solution was then dried by azetropic removal of water using MeTHF. This was accomplished by the addition of 2 mL of MeTHF and then concentration (about 2 mL) of the resulting solution under reduced, pressure at 70 C. The resulting solution is then cooled to 0 C in an ice bath and then a-aminoisobutyric acid chloride hydrochloride (0.04 g, 0.25mmol, 1.0 equiv. ) is added under nitrogen. The reaction mixture is stirred for 3 hours at which point the solid is collected by filtration and washed with MeTHF (2 X 2 mL). The solid is then dried under reduced pressure to yield the product as a yellow powder (171 mg, 0.2425 mmol, 97% overall yield).

  • 6
  • [ 75747-14-7 ]
  • retaspimycin hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Compound 1 (0.450 g, 0.768 mmol, 1.0 eq) was dissolved in DCM (50 mL) and stirred with a 10% aqueous solution of sodium hydrosulfite (50 mL). The solution was stirred for 30 min. The organic layer was collected, dried over Na2SO4, filtered and transferred to a round bottom flask. To this solution was added a solution of HCl in dioxane (4 N, 0.211 mL, 1.1 eq). The resulting mixture was allowed to stir under nitrogen for 30 min. A yellow solid slowly crashed out of solution. The yellow solid was purified by recrystallization form MeOH/EtOAc to yield 0.386 g of compound 2.
Compound of Formula (1) (0.450 g, 0. 768 mmol, 1.0 equiv) is dissolved in dichloromethane (50 mL) and stirred with a 10% aqueous solution of sodium hydrosulfite (50 mL). The solution is stirred for 30 minutes. The organic layer was collected, dried over Na2SO4, filtered and transferred to a round bottom flask. To this solution was added a solution of HC1 in dioxane (4 N, 0.211 mL, 1.1 equiv. ). The resulting mixture was allowed to stir under nitrogen for 30 minutes. A yellow solid slowly crashed out of solution. The yellow solid was purified by recrystallization form MeOH/EtOAc to yield 0.386 g of the IPI-504 (15).
Anhydrous ethyl acetate (170 mL) was added to a flask followed by <strong>[75747-14-7]17-AAG</strong> (8.41 g, 1.44 mmol, 1 equiv). The resultant purple mixture was stirred vigorously under nitrogen. A freshly prepared solution of 10% Na2S204 (aq) (1.682 g in 170 mL of deionized water, 10.1 mmol, 7 equiv) was added and the mixture stirred vigorously for 70 min. The color changed from purple to orange indicating a complete reaction. The layers were allowed to separate and the bottom aqueous layer was removed using a separatory funnel. The organic layer was dried with MgS04. The drying agent was removed by filtration. The filtrate was transferred to a rotary evaporator flask. Ethyl acetate (50 mL) was used, in portions, to wash the MgS04 pad and the wash filtrate was also added to the rotary evaporator flask. The orange-brown mixture was concentrated on the rotary evaporator to an oil. The remaining ethyl acetate was removed under vacuum. While this mixture was concentrated, a 5.3 M solution of HCl in ethyl acetate was prepared. Ethyl acetate (16.8 mL) was added to an Erlenmeyer flask and HC1 gas bubbled into the stirring mixture for 1 h (with cooling, acetone/wet ice) to achieve saturation. The solution was then warmed to room temperature under a head space of nitrogen. The oil was dissolved in acetone (252 mL) and transferred to a reaction flask equipped with an addition funnel, a stirrer, a thermometer, and a nitrogen atmosphere. The combined filtrate and rinse were acidified over 5 min to a final pH of 2.5. The resulting slurry was stirred for 18 min at ambient temperature and the solids were then isolated by filtration and washed twice with acetone (84 mL). The solid was then dried under reduced pressure to yield the product
17-Allylamino-17-Demethoxygeldanamycin (10.0 g, 17. 1 mmol) in ethyl acetate (200 mL) was stirred vigorously with a freshly prepared solution of 10% aqueous sodium hydrosulfite (200 mL) for 2 h at ambient temperature. The color changed from dark purple to bright yellow, indicating a complete reaction. The layers were separated and the organic phase was dried with magnesium sulfate (15 g). The drying agent was rinsed with ethyl acetate (50 mL). The combined filtrate was acidified with 1. 5 M hydrogen chloride in ethyl acetate (12 mL) to pH 2 over 20 min. The resulting slurry was stirred for 1.5 h at ambient temperature. The solids were isolated by filtration, rinsed with ethyl acetate (50 mL) and dried at 40 C, 1 mm Hg, for 16 h to afford 9.9 g (91%) of off-white solid. Crude hydroquinone hydrochloride (2.5 g) was added to a stirred solution of 5% 0.01 N aq. hydrochloric acid in methanol (5 mL). The resulting solution was clarified by filtration then diluted with acetone (70 mL). Solids appeared after 2-3 min. The resulting slurry was stirred for 3 h at ambient temperature, then for 1 h at 0-5 C. The solids were isolated by filtration, rinsed with acetone (15 mL) and dried
Example 1: Preparation of the hydrochloride salt of the hydroquinone of 17- AAG[0073] <strong>[75747-14-7]17-AAG</strong> (0.450 g, 0.768 mmol, 1.0 equiv) is dissolved in dichloromethane (50 rnL) and stirred with a 10% aqueous solution of sodium hydrosulfte (50 mL). The solution is stirred for 30 minutes. The organic layer was collected, dried over Na2SO4, filtered and transferred to a round bottom flask. To this solution was added a solution of HCl in dioxane (4 N, 0.211 mL, 1.1 equiv.). The resulting mixture was allowed to stir under nitrogen for 30 minutes. A yellow solid slowly crashed out of solution. The yellow solid was purified by recrystallization form MeOH/EtOAc to yield 0.386 g of the hydroquinone HCl salt (2).

  • 7
  • [ 75747-14-7 ]
  • C31H45N3O8*H2O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Compound of Formula (1) (0. 30 g, 0.5 mmol, 1.0 equiv) is dissolved in MTBE (3 mL) and stirred with a 20% aqueous solution of sodium hydrosulfite (2 mL). The solution is stirred for 60 minutes. The organic layer was collected, washed with brine, and transferred to a round bottom flask. This solution was cooled-5 C and put under nitrogen. To this solution was added a solution of H2S04 in denatured ethanol (0.50 mmol of H2SO4 in 0.5 mL of EtOH) dropwise. The resulting mixture was allowed to stir under nitrogen and warm to RT. The yellow slurry was stirred for an additional 30 minutes at RT and then was concentrated. MTBE (7 mL) was added and the suspension was filtered. The yellow solid that was collected was washed with MTBE and dried under reduced pressure to yield 0.30 g of the desired product.
Example 3: Preparation of the sulfate salt of the hydroquinone of 17- AAG[0075] <strong>[75747-14-7]17-AAG</strong> (0.30 g, 0.5 mmol, 1.0 equiv) is dissolved in MTBE (3 niL) and stirred with a 20% aqueous solution of sodium hydrosulfite (2 rnL). The solution is stirred for 60 minutes. The organic layer was collected, washed with brine, and transferred to a round bottom flask. This solution was cooled -5 C and put under nitrogen. To this solution was added a solution Of H2SO4 in denatured ethanol (0.50 mmol Of H2SO4 in 0.5 mL of EtOH) dropwise. The resulting mixture was allowed to stir under nitrogen and warm to RT. The yellow slurry was stirred for an additional 30 minutes at RT and then was concentrated. MTBE (7 mL) was added and the suspension was filtered. The yellow solid that was collected was washed with MTBE and dried under reduced pressure to yield 0.30 g of the desired product 4.
  • 8
  • [ 75747-14-7 ]
  • C31H45N3O8*H3O4P [ No CAS ]
YieldReaction ConditionsOperation in experiment
Compound of Formula (1) (0.30 g, 0.5 mmol, 1.0 equiv) is dissolved in DCM (6 mL) and stirred with a 10% aqueous solution of sodium hydrosulfite (3.5 mL). The solution is stirred for 60 minutes. The organic layer was collected, washed with brine, and 1.2 mL (calc 0.1 mmol of hydroquinone) transferred to a round bottom flask. This solution was put under nitrogen. To this solution was added a solution of H3P04 in denatured IPA (0.100 mmol of H3P04 in 0.25 mL of IPA) dropwise. The resulting mixture was allowed to stir under nitrogen for 1 hour, at which point the mixture was concentrated and the crude mass was reslurried from EtOAc/MTBE. The solid was collected by filtration and dried under reduced pressure to yield 0.050 g of the desired product.
Example 6: Preparation of the hydrogen phosphate salt of the hydroquinone of 17- AAG[0078] <strong>[75747-14-7]17-AAG</strong> (0.30 g, 0.5 mmol, 1.0 equiv) is dissolved in DCM (6 niL) and stirred with a 10% aqueous solution of sodium hydrosulfite (3.5 rnL). The solution is stirred for 60 minutes. The organic layer was collected, washed with brine, and 1.2 mL (calc 0.1 mmol of hydroquinone) transferred to a round bottom flask. This solution was put under nitrogen. To this solution was added a solution Of HsPO4 in denatured IPA (0.100 mmol Of HsPO4 in 0.25 mL of IPA) dropwise. The resulting mixture was allowed to stir under nitrogen for 1 hour, at which point the mixture was concentrated and the crude mass was reslurried from EtOAc/MTBE. The solid was collected by filtration and dried under reduced pressure to yield 0.050 g of the desired product 7.
  • 9
  • [ 75747-14-7 ]
  • [ 857402-23-4 ]
YieldReaction ConditionsOperation in experiment
90% With sodium dithionite; water; In ethyl acetate; for 0.5h; 17-Allylaminogeldanamycin (1) (0.548 g, 0.937 mmol, 1.0 equiv) was dissolved in 12.0 mL ethyl acetate and stirred with an aqueous solution of sodium hydrosulfite (sodium hydrosulfite (1.2 g) in water (12 mL)). The deep purple solution turned yellow after 5 min and the mixture was stirred for an additional 25 min. The organic layer was collected, dried over MgSO4, and concentrated under reduced pressure to yield the desired hydroquinone 2 (0.500 g, 0.85 mmol, 90% yield).
~ 85% With sodium dithionite; water; In ethyl acetate; at 20℃; for 2h; Hydroquinone form of (4): 17-Allylamino-17-demethoxy-18, 21-dihydrogeldanamycin. (DHAAG). 17-Allyamino-17-demethoxygeldanamycin (3.2 mg, 5. 5 umol) was dissolved in ethyl acetate (3.0 ml), then an aqueous solution (2.5 ml) of sodium dithionite (-85%, 0.50 g, 2.4 mmol) was added. The mixture was stirred at room temperature for 2 hours. Under nitrogen protection, the light yellow organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the product as a dark yellow solid (3.0 mg, 93%).'H NMR (done in CDC13 following exchangeable hydrogen exchange with D2O-Na2S204, 500 MHz) 6 7.66 (bs, 1H), 6.87 (bd, J= 11.5 Hz, 1H), 6.39 (bdd, J= 11.5, 11.0 Hz, 1H), 6.04-5. 96 (ddt, J= 16.0, 10.0, 5.5 Hz, 1H), 5.77 (bd, J= 9.5 Hz, 1H), 5.68 (bdd, J= 11.0, 10.0 Hz, 1H), 5.29 (bd, J= 16.0 Hz, 1H), 5.13 (bd, J= 10.0 Hz, 1H), 5.01 (s, 1H), 4.30 (bd, J= 10.0 Hz, 1H), 3.56 (bdd, J= 9.0, 2.0 Hz, 1H), 3.47 (bd, J= 5.5 Hz, 2H), 3.37-3. 32 (m, 1H), 3.32 (s, 3H), 3.23 (s, 3H), 2.80-2. 71 (m, 1H), 2.61-2. 51 (m, 1H), 1.90 (bs, 1H), 1.79-1. 72 (m, 7H), 1.66-1. 61 (m, 1H), 0.96 (d, J= 6.5 Hz, 3H), 0.85 (d, J= 7.0 Hz, 3H).
74.0% With sodium dithionite; water; In ethyl acetate; at 22℃; for 1h;Product distribution / selectivity; Example 11. PREPARATION OF Pi-ALLYLAMINO-GELDANAMYCIN HYDROQUINONE (17- AAG-HQ); [00213] Example HA. To a solution of 17-allylamino-geldanamycin (<strong>[75747-14-7]17-AAG</strong>) (3.03 grams, 5.17 mmol, 1.0 equiv) in EtOAc (60 rnL) at 22 0C was added sodium hydrosulfite (Na2S2O4) (25 g in 125 mL; 1.1 M). The biphasic mixture was stirred vigorously until the purple mixture turned yellow (60 min) and a precipitate formed in the organic layer (60 h). The organic layer was filtered and the precipitate was washed with several aliquots of ethyl acetate (25 mL, 3x) and water (25 mL, 3x). The organic filtrate was reserved for use in the preparation of <strong>[75747-14-7]17-AAG</strong>-HQ of Example HB (see below). The washed precipitate was collected and dried under vacuum to obtain 17-allylamino-geldanamycin hydroquinone (17-- 55 -B3678215.2 AAG-HQ) of Example HA as a bright yellow solid (654.0 mg, 1.11 mmol, 21.5 % Yield). Percent Purity (HPLC-UV): 98 %.; [00214] Example HB. To the organic filtrate from Example 1 IA was added an aqueous solution of sodium hydrosulfite (Na2S2O4) (20 g in 100 mL; 1.1M). The biphasic mixture was stirred vigorously for 1 h to ensure full conversion to 17- AAG-HQ. The yellow organic layer was separated and washed with 100 mL NaCl and dried with MgSO4. The organic solution was filtered and the drying agent was rinsed with 100 mL EtOAc. The organic layers were combined and the solution was concentrated under reduced pressure to 17-allylamino-geldanamycin hydroquinone (17- AAG-HQ) of Example HB as a rusty yellow solid (2.25 grams, 3.38 mmol, 74.0%). Percent Purity (HPLC-UV): 97 %. [00215] Comparison of Examples HA and HB. When compared to <strong>[75747-14-7]17-AAG</strong>-HQ of Example HB, <strong>[75747-14-7]17-AAG</strong>-HQ of Example HA shows greater stability over a period of time when kept at 4O0C and 75% relative humidity (RH) (see Figure 12 and Table 8). The greater stability can be attributed to a higher sulfur content of <strong>[75747-14-7]17-AAG</strong>-HQ of Example HA as compared to the sulfur content of <strong>[75747-14-7]17-AAG</strong>-HQ of Example 1 IB (See Table 7).
With sodium dithionite; water; In ethyl acetate; at 20℃; for 1h; 17-Allylamino-17-Demethoxygeldanamycin (0. 350 g, 0.598 mmol) in ethyl acetate (7 mL) was stirred vigorously with a freshly prepared solution of 10% aqueous sodium hydrosulfite (7 mL) for 1 h at ambient temperature. The color changed from dark purple to bright yellow, indicating a complete reaction. The layers were separated and the organic phase was dried with magnesium sulfate (1 g). The drying agent was rinsed with ethyl acetate (1 mL). The combined organic layers were stirred at room temperature and to it was added triphosgene (0.079 g, 0.239 mmol). A precipitate formed and the resulting mixture was allowed to stir for 2 hr. At which point the solid was filtered off and the organic solution was concentrated. The crude product was purified by column chromatography to yield 17 mg of the desired product.

  • 10
  • [ 75747-14-7 ]
  • BrH*C31H45N3O8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% 17-Allylamino-17-Demethoxygeldanamycin (1.0 g, 1.71 mmol) in ethyl acetate (20 mL) was stirred vigorously with a freshly prepared solution of 10% aqueous sodium hydrosulfite (2g in 20 mL water) for 30 minutes at ambient temperature. The color changed from dark purple to bright yellow, indicating a complete reaction. The layers were separated and the organic phase was dried with magnesium sulfate (1 g). The reaction solvent was collected and the drying agent was rinsed with ethyl acetate (1 mL). The combined filtrate was cooled to 0 C and acidified with 1.5 M hydrogen bromide in ethyl acetate until a precipitate formed. The resulting slurry was stirred for 30 minutes at ambient temperature. The solids were isolated by filtration, rinsed with ethyl acetate (1 mL) and dried at 40 C, 1 mm Hg, for 16 h to afford 0. 352 g (31%) of off-white solid.
31% Example 2: Preparation of the hydrobromide salt of the hydroquinone of 17- AAG[0074] <strong>[75747-14-7]17-AAG</strong> (1.0 g, 1.71 mmol) in ethyl acetate (20 niL) was stirred vigorously with a freshly prepared solution of 10% aqueous sodium hydrosulfite (2g in 20 rnL water) for 30 minutes at ambient temperature. The color changed from dark purple to bright yellow, indicating a complete reaction. The layers were separated and the organic phase was dried with magnesium sulfate (1 g). The reaction solvent was collected and the drying agent was rinsed with ethyl acetate (1 mL). The combined filtrate was cooled to 0 C and acidified with 1.5 M hydrogen bromide in ethyl acetate until a precipitate formed. The resulting slurry was stirred for 30 minutes at ambient temperature. The solids were isolated by filtration, rinsed with ethyl acetate (1 mL) and dried at 40 0C, 1 mm Hg, for 16 h to afford 0.352 g (31%) of 3 as a off-white solid.
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol; at 20 - 80℃;Purification / work up; An alternative method of purification is to dissolve the crude <strong>[75747-14-7]17-AAG</strong> from example 1 in 800 mL of 2-propyl alcohol (isopropanol) at 80 C. and then cool to room temperature. Filtration followed by drying at 45 C. for 8 hr gives 44.6 g (72.36 mmol) of <strong>[75747-14-7]17-AAG</strong> as purple crystals (90% yield, >99% pure by HPLC monitored at 254 nm). MP 147-175 C. as determined using differential scanning colorimetry (DSC). 1H NMR and HPLC are consistent with the desired product.
In ethanol; water; at 25℃;Purification / work up; An alternative method of purification is to slurry the <strong>[75747-14-7]17-AAG</strong> product from example 2 in 400 mL of H2O:EtOH (90:10) at 25 C., filtered and dried at 45 C. for 8 hr to give 42.4 g (68.6 mmol) of <strong>[75747-14-7]17-AAG</strong> as purple crystals (95% yield, >99% pure by HPLC monitored at 254 nm). MP 147-175 C. 1H NMR and HPLC are consistent with the desired product.
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