* 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.
In a 500mL two neck round-bottomed flask equipped with a magnetic stir bar was dissolved amide 5 (3.40g, 8.13mmol) in THF (60mL) and cooled to −78°C. While stirring at −78°C, potassium tert-butoxide (1.0M solution in THF, 8.95mL, 8.94mmol, 1.10equiv) was added. The reaction mixture was warmed to −10°C and stirred for 30min. The reaction mixture was cooled to −78°C and diphenyl chlorophosphate (2.02mL, 9.76mmol) was added to the reaction mixture. The resulting mixture was warmed to −10°C and stirred at this temperature for 45min. Acetylhydrazide (0.90, 12.20mmol, 1.50equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature. After 1h, 1-butanol (70mL) was added to the reaction mixture, which was heated to 90°C. After 1h, all solvents were removed under reduce pressure. The residue was dissolved in CH2Cl2 and washed with saturated aq. NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain crude (+)-JQ1, which was purified by flash column chromatography on silica gel (0–100percent ethyl acetate in hexanes) to afford (+)-JQ1 (3.04g, 82percent) as a white solid and with a 91:9 er (determined with Supercritical Fluid Chromatography (SFC) using the CHIRALPAK AS-H column, CO2–EtOH (3:1), 210nm, tR (R-enantiomer) 1.62min, tR (S-enantiomer) 3.51min). This product was further purified by preparative SFC using a CHIRALPAK AS-H column to obtain (+)-JQ1 (S-enantiomer) with >99percent ee. The spectral data of (+)-JQ1 matched with those described in the literature6 with the exception of the optical rotation. [α]D22 +41 (c 0.50, CHCl3), (Lit. [α]D22 +55 (c 0.50, CHCl3);12 (−)-JQ1: >99percent ee, [α]D22 −39 (c 0.55, CHCl3), (Lit. [α]D22 −55 (c 0.50, CHCl3).6
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -78 - 23℃; for 0.5 h; Stage #2: With diethyl chlorophosphate In tetrahydrofuran at -10℃; for 0.75 h; Stage #3: at 23 - 90℃; for 2 h;
Potassium tert-butoxide (1.0 M solution in THF, 0.3 ml, 0.30 mmol, 1.10 equiv) was added to a solution of S5 (114 mg, 0.27 mmol, 1 equiv) in THF (1.8 ml, 0.15 M) at -78 °C. The reaction mixture was warmed to -10 °C, and stirred at 23 °C for 30 min. The reaction mixture was cooled to -78 °C. Diethyl chlorophosphate (0.047 ml, 0.32 mmol, 1.20 equiv) was added to reaction mixture 22. The resulting mixture was warmed to -10 °C over 45 min. Acetic hydrazide (30 mg, 0.40 mmol, 1.50 equiv) was added to reaction mixture. The reaction mixture was stirred at 23 °C. After 1 h, 1-butanol (2.25 ml) was added to reaction mixture, which was heated to 90 °C. After 1 h, all solvents were removed under reduce pressure. The residue was purified with flash column chromatography (Combiflash system, 4 g silica gel, gradient 0 to 100 percent ethyl acetate-hexanes) to afford (+)-JQl (114 mg, 92 percent) as white solid with 90 percent enantiomeric purity (determined with Berger Supercritical Fluid Chromatography (SFC) using AS-H column, 85 percent hexanes- methanol, 210 nm, tR (R- enantiomer) = 1.59 min, tR (S-enantiomer) = 3.67 min). The product was further purified by chiral preparative HPLC (Agilent High Pressure Liquid Chromatography using an OD-H column) to provide the S-enantiomer in greater than 99 percent ee.1H NMR (600 MHz, CDC13, 25 °C) δ 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H),4.54 (t, J = 6.6 MHz, 1H), 3.54-3.52 (m, 2H), 2.66 (s, 3H), 2.39 (s, 3H), 1.67 (s, 3H), 1.48 (s, 9H).13C NMR (150 MHz, CDC13, 25 °C) δ 171.0, 163.8, 155.7, 150.0, 136.9, 131.1, 130.9, 130.6, 130.3, 128.9, 81.2, 54.1, 38.1, 28.4, 14.6, 13.5, 12.1.HRMS(ESI) calc'd for C2iH24ClN203S [M+H]+: 457.1460, found 457.1451 m/z.TLC (EtOAc), Rf: 0.32 (UV)[a]22D = + 75 (c 0.5, CHCl3)
Stage #1: With hydrazine hydrate In tetrahydrofuran at 23℃; for 1 h; Stage #2: at 120℃; for 2 h;
Hydrazide (0.015 mL, 0.45 mmol, 1.25 equiv) was added to compound 9 (158 mg, 0.36 mmol, 1 equiv) in THF. The reaction mixture was heated to 23 ° C and stirred for 1 h.The solvent was removed by distillation under reduced pressure, and the resulting hydrazide was used without purification. The hydrazide was dissolved in a 2: 3 volume ratio of trimethyl orthoacetate and toluene solution (6 mL, 0.06 M).The reaction mixture was heated to 120 ° C. After 2 h, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to give Compound 10 (14 mg, 85percent yield).
In a 500mL two neck round-bottomed flask equipped with a magnetic stir bar was dissolved amide 5 (3.40g, 8.13mmol) in THF (60mL) and cooled to −78°C. While stirring at −78°C, potassium tert-butoxide (1.0M solution in THF, 8.95mL, 8.94mmol, 1.10equiv) was added. The reaction mixture was warmed to −10°C and stirred for 30min. The reaction mixture was cooled to −78°C and diphenyl chlorophosphate (2.02mL, 9.76mmol) was added to the reaction mixture. The resulting mixture was warmed to −10°C and stirred at this temperature for 45min. Acetylhydrazide (0.90, 12.20mmol, 1.50equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature. After 1h, 1-butanol (70mL) was added to the reaction mixture, which was heated to 90°C. After 1h, all solvents were removed under reduce pressure. The residue was dissolved in CH2Cl2 and washed with saturated aq. NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain crude (+)-JQ1, which was purified by flash column chromatography on silica gel (0–100percent ethyl acetate in hexanes) to afford (+)-JQ1 (3.04g, 82percent) as a white solid and with a 91:9 er (determined with Supercritical Fluid Chromatography (SFC) using the CHIRALPAK AS-H column, CO2–EtOH (3:1), 210nm, tR (R-enantiomer) 1.62min, tR (S-enantiomer) 3.51min). This product was further purified by preparative SFC using a CHIRALPAK AS-H column to obtain (+)-JQ1 (S-enantiomer) with >99percent ee. The spectral data of (+)-JQ1 matched with those described in the literature6 with the exception of the optical rotation. [α]D22 +41 (c 0.50, CHCl3), (Lit. [α]D22 +55 (c 0.50, CHCl3);12 (−)-JQ1: >99percent ee, [α]D22 −39 (c 0.55, CHCl3), (Lit. [α]D22 −55 (c 0.50, CHCl3).6
Potassium tert-butoxide (1.0 M solution in THF, 0.3 ml, 0.30 mmol, 1.10 equiv) was added to a solution of S5 (114 mg, 0.27 mmol, 1 equiv) in THF (1.8 ml, 0.15 M) at -78 C. The reaction mixture was warmed to -10 C, and stirred at 23 C for 30 min. The reaction mixture was cooled to -78 C. Diethyl chlorophosphate (0.047 ml, 0.32 mmol, 1.20 equiv) was added to reaction mixture 22. The resulting mixture was warmed to -10 C over 45 min. Acetic hydrazide (30 mg, 0.40 mmol, 1.50 equiv) was added to reaction mixture. The reaction mixture was stirred at 23 C. After 1 h, 1-butanol (2.25 ml) was added to reaction mixture, which was heated to 90 C. After 1 h, all solvents were removed under reduce pressure. The residue was purified with flash column chromatography (Combiflash system, 4 g silica gel, gradient 0 to 100 % ethyl acetate-hexanes) to afford (+)-JQl (114 mg, 92 %) as white solid with 90 % enantiomeric purity (determined with Berger Supercritical Fluid Chromatography (SFC) using AS-H column, 85 % hexanes- methanol, 210 nm, tR (R- enantiomer) = 1.59 min, tR (S-enantiomer) = 3.67 min). The product was further purified by chiral preparative HPLC (Agilent High Pressure Liquid Chromatography using an OD-H column) to provide the S-enantiomer in greater than 99 % ee.1H NMR (600 MHz, CDC13, 25 C) delta 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H),4.54 (t, J = 6.6 MHz, 1H), 3.54-3.52 (m, 2H), 2.66 (s, 3H), 2.39 (s, 3H), 1.67 (s, 3H), 1.48 (s, 9H).13C NMR (150 MHz, CDC13, 25 C) delta 171.0, 163.8, 155.7, 150.0, 136.9, 131.1, 130.9, 130.6, 130.3, 128.9, 81.2, 54.1, 38.1, 28.4, 14.6, 13.5, 12.1.HRMS(ESI) calc'd for C2iH24ClN203S [M+H]+: 457.1460, found 457.1451 m/z.TLC (EtOAc), Rf: 0.32 (UV)[a]22D = + 75 (c 0.5, CHCl3)
With potassium tert-butylate; diethyl chlorophosphate; In tetrahydrofuran;
This chiral triazole-fused thiphenodiazepine acetic acid was prepared according to the literature using the synthetic scheme above (Nature 468, 1067-1073, 2010; FN AS 113, 7124- 7129, 2016), NMR (400 MHz, DMSO_d6): delta 1.63 (s, 3H), 2.42 (s, 3H), 2.60 (s, 3H), 3.31-3.41 (m, 2H), 4.45 (t, J = 7.2 Hz, 1H), 7.45-7.49 (m, 4H); LC/MS 401.1 [M+l]+
A solution of the product from stage 4 (20.0 g) in tetrahydrofuran (320 ml) was cooled to - 40 C and treated dropwise over 1 h with a 25% toluene solution of potassium amylate (27.3 g). After stirring at -40 C for 1 h, a solution of diphenyl chlorophosphate (16.8 g) in tetrahydrofuran was added over 0.3 h. The reaction mixture was warmed to -10 C over 1.5 h and stirred at this temperature for 0.5 h.A suspension of acetyl hydrazide (5.1 g) in toluene (30 ml) was added with the aid of additional toluene (30 ml) and the mixture was allowed to warm over 0.5 h to 20 C. Stirring was continued for 1 h, more toluene (200 ml) added and the reaction mixture was heated at 80 C for 1 h. Solvent was removed under reduced pressure to a residual volume of ca. 400 ml, water (80 ml) was added and the two phase mixture was stirred at 20 C for 0.3h. The organic layer was separated and washed with 0.1N aqueous sulphuric acid (80 ml), 5% aqueous sodium carbonate (80 ml) and water (80 ml) then evaporated under reduced pressure, yielding crude stage 5 product (-25 g) which was used directly in the subsequent step. The deprotection can also be conducted with potassium tert.-butoxide and/or at temperatures of up to 20C with essentially no depreciation on yield or enantiomeric purity.
(1R,5S)-tert-butyl 3-({2-[(S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetyl}amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate[ No CAS ]
N-[(1R,5S)-9-azabicyclo[3.3.1]non-3-yl]-2-[(S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetamide[ No CAS ]
A solution of 1.6 g (3.5 mmol) of tert-butyl[(S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate in 25 ml HCl in dioxane (4N) was stirred overnight at RT. The solvent was removed completely under vacuum and the title compound was obtained as a solid. 1.53 g. [0450] 1H-NMR (400 MHz, RT, DMSO-d6): delta=1.6 (s, 3H), 2.39 (s, 3H), 2.61 (s, 3H), 3.31 (dd, 1H), 3.41 (dd, 1H), 4.46 (t, 1H), 4.56 (bs), 7.41 (d, 2H), 7.47 (d, 2H)
(S)-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With formic acid; at 20℃; for 75h;
JQ1 (1.0 g, 2.19 mmol, 1 eq) was dissolved in formic acid (11 mL, 0.2 M) at room temperature and stirred for 75 hours. The mixture was concentrated under reduced pressure to giveyellow solid (0.99 g, quant yield) that was used without purification. ?H NMR(400 MHz,Methanol-d4) 7.50-7.36 (m, 4H), 4.59 (t, J= 7.1 Hz, 1H), 3.51 (d, J= 7.1 Hz, 2H), 2.70 (s, 3H), 2.45 (s, 3H), 1.71 (s, 3H). LCMS 401.33 (M+H).
100%
With formic acid; at 20℃; for 75h;
JQ1 (1.0 g, 2.19 mmol, 1 eq) was dissolved in formic acid (11 mL, 0.2 M) at room temperature and stirred for 75 hours. The mixture was concentrated under reduced pressure to give a yellow solid (0.99 g, quant yield) that was used without purification. 1H NMR (400 MHz, Methanol-d4) delta 7.50- 7.36 (m, 4H), 4.59 (t, J = 7.1Hz, 1H), 3.51 (d, J = 7.1Hz, 2H), 2.70 (s, 3H), 2.45 (s, 3H), 1.71 (s, 3H). LCMS 401.33 (M+H).
100%
With trifluoroacetic acid; In dichloromethane; at 20℃; for 5h;
The JQ1 18 (1 g, 2.2 mmol) was dissolved in 40% TFA/DCM solution(24 mL) and stirred at room temperature for 5 h. The reactionmixturewas concentrated and dissolved in EtOAc. The organic layerwas washed with water and brine, dried over MgSO4, andconcentrated. The residue was purified by column chromatographyto give the compound 19 (900 mg, quant.) as a yellow solid. 1H NMR(300 MHz, Chloroform-d) delta 7.45 (d, J 8.6 Hz, 2H), 7.36 (d,J 8.6 Hz, 2H), 6.36 (s, 2H), 4.63 (t, J 6.8 Hz, 1H), 3.81e3.55 (m,2H), 2.74 (s, 3H), 2.44 (s, 3H), 1.72 (s, 3H). LC/MS (M H) (m/z)400.9, (M H)- (m/z) 398.9; mp 90e93 C
96%
With formic acid; at 25℃; for 18h;
(+)-JQ-l (50 mg, 109 umol) was dissolved in formic acid (3 ml) and stirred for 18 h at 25 C. After addition of water the reaction mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to obtain the title compound which was directly used for the next reaction step. Yield 42. 1 mg (96 %).
96%
With formic acid; at 25℃; for 18h;
(+)-JQ-1 (50 mg, 109 jimol) was dissolved in formic acid (3 ml) and stirred for 18 h at25 C. After additionof water the reaction mixture was extracted three times with dichloromethane. The combined organic layerswere dried over magnesium sulfate and evaporated to dryness to obtain the title compound which was directly used for the next reaction step. HPLC analysis (METHOD 2): it = 3.3 14 mm, mlz = 401.0, [M+Hj. Yield 42.1 mg (96 %).
94%
With water; sodium hydroxide; In ethanol; at 100℃; for 2h;
Compound 10 (0.46 g, 1 mmol) was weighed into ethanol and 200 mL of the mass concentration was added 20% NaOH solution, heated to 100 C, high temperature reflux 2h. After the completion of the reaction, the mixture was cooled to room temperature, 1 M hydrochloric acid was added, the pH was adjusted to 6-7, The organic layer was washed three times with saturated brine to give Compound 11 (0.38 g, yield 94%).
With formic acid; at 20℃; for 75h;
JQ1 (l .O g, 2.19 mmol, 1 eq) was dissolved in formic acid (11 mL, 0.2 M) at room temperature and stirred for 75 hours. The mixture was concentrated under reduced pressure to give a yellow solid (0.99 g, quant yield) that was used without purification. NMR (400 MHz, Methanol-) delta 7.50 - 7.36 (m, 4H), 4.59 (t, J = 7.1 Hz, 1H), 3.51 (d, J = 7.1 Hz, 2H), 2.70 (s, 3H), 2.45 (s, 3H), 1.71 (s, 3H). LCMS 401.33 (M+H).
With formic acid;
This chiral triazole-fused thiphenodiazepine acetic acid was prepared according to the literature using the synthetic scheme above (Nature 468, 1067-1073, 2010; FN AS 113, 7124- 7129, 2016), NMR (400 MHz, DMSO_d6): delta 1.63 (s, 3H), 2.42 (s, 3H), 2.60 (s, 3H), 3.31-3.41 (m, 2H), 4.45 (t, J = 7.2 Hz, 1H), 7.45-7.49 (m, 4H); LC/MS 401.1 [M+l]+
With formic acid; at 23℃; for 72h;
Exemplary subunit A-, (S)-JQ1, was synthesized as previously described in Filippakopoulos, P. et al., Nature 468, 1067-1073 (2010), which is incorporated herein by reference. As shown in Scheme 1, following the synthesis of (S)-JQ1, the tert-butyl group was hydrolyzed with formic acid (23 C., 72 h) to afford (S)-JQ1 acid. The JQ1 acid was then activated using 1-Hydroxy-7-azabenzotriazole (HOAt) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), then coupled to linker H2N-PEG6-CH2CH2COOH (23 C., 4 h) to afford (S)-JQ1-PEG6. The resulting molecule was purified by reverse-phase HPLC and verified by MALDI-TOF mass spectrometry. Fractions that showed clean molecule were frozen and lyophilized to afford an oil.
With formic acid; at 20℃; for 75h;
JQ1 (1.0 g, 2.19 mmol, 1 eq) was dissolved in formic acid (11 mE, 0.2 M) at room temperature and stirred for 75 hours. The mixture was concentrated under reduced pressure to give a yellow solid (0.99 g, quant yield) that was used without purification. ?H NMR (400 MHz, Methanol-d4) oe 7.50-7.36 (m, 4H), 4.59 (t, J=7.1 Hz, 1H), 3.51 (d, J=7.1 Hz, 2H), 2.70 (s, 3H), 2.45 (s, 3H), 1.71 (s, 3H). ECMS 401.33 (M+H).
10.4 g
The product from stage 5 (24.6 g; prepared as described in Example 5.1; 24.6 g) was dissolved in trifluoroacetic acid (80 ml) and the solution was stirred at 20 C for 2 h. The solvent was removed under reduced pressure and the residue was taken up in toluene (200 ml). Excess trifluoroacetic acid was eliminated through concentration under reduced pressure.The crude product, as the trifluoroacetate salt, was taken up in water (200 ml) and treated with 28% aqueous sodium hydroxide (35 g) rendering a pH ca. 10. t-Butyl methyl ether (200 ml) was added and the pH of the aqueous phase was adjusted to pH 7.3-7.5 with 5% aqueous sulphuric acid (50 g). After vigorously stirring the two phase mixture for 0.3 h, the organic layer was separated and to the aqueous phase containing the product was added t-butyl methyl ether (200 ml). The pH of the aqueous phase was adjusted further to pH 6.4-6.6 with 5% aqueous sulphuric acid (10 g) and the mixture was stirred for 0.3 h. The organic layer containing residual stage 4 deprotected product acid was separated and the aqueous phase containing the product was extracted with t-butyl methyl ether (ca. six times) until the level of contaminant acid in the aqueous layer was The product was suspended in isopropanol (60 ml), residual dichloromethane removed by concentration at 40 C/40 mb and the residue resuspended in isopropanol (60 ml). The mixture was heated to 65 C, stirred until a clear, orange solution was obtained, then allowed to cool to 20 C whereupon the product partially precipitated. The suspension was stirred for 1 h, diluted over lh with n-heptane (120 ml) and stirred for 2 h at 20 C. The product was filtered, washed with 10% isopropanol in heptane (50 ml) and dried at 60 C/10 mb for 16 h, furnishing stage 6 product (10.4 g, ca. 55% over two steps, ee 100%) as a pale yellow powder.
With formic acid; at 23℃; for 72h;
Exemplary subunit A-, (S)-JQ1, was synthesized as previously described in Filippakopoulos, P. et al., Nature 468, 1067-1073 (2010), which is incorporated herein by reference. As shown in Scheme 5 (FIG. 16), following the synthesis of (S)-JQ1, the tert-butyl group was hydrolyzed with formic acid (23 C., 72 h) to afford (S)-JQ1 acid. The JQ1 acid was then activated using HOAt (1-Hydroxy-7-azabenzotriazole) and HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), then coupled to linker H2N-PEG6-CH2CH2COOH (23 C., 4 h) to afford (S)-JQ1-PEG6. The resulting molecule was purified by reverse-phase HPLC and verified by MALDI-TOF mass spectrometry. Fractions that showed clean molecule were frozen and lyophilized to afford an oil. (0260) Table 4 illustrates the identity and purity of (S)-JQ1-PEG6 using MALDI-TOF mass spectrometry and analytical HPLC. [table-us-00005-en] TABLE 4 Mass spectrometric of (S)-JQ1-PEG6. Mass Mass Molecule Molecular formula Calculated Observed (S)-JQ1-PEG6 C34H47ClN5O9S+ 736.28 736.95 (0261) As shown in Scheme 6 (FIG. 17), (S)-JQ1-PEG6 was activated with HOAt and HATU in N,N-diisopropyethylamine (DIEA) and dimethylformamide (DMF), then coupled to control polyamides 1 or 3 to yield the control polyamide 1-PEG6-JQ1 (control conjugate 1) and control polyamide 3-PEG6-JQ1 (Agent 4), respectively. The conjugates were purified by reverse-phase HPLC and analyzed by MALDI-TOF mass spectrometry (Table 5). Fractions that showed clean conjugate without contaminants were frozen in liquid nitrogen and lyophilized to afford a white or off white powder. (0262) Table 5 illustrates the identity and purity of control conjugate 2 and Agent 4 using MALDI-TOF mass spectrometry and analytical HPLC. [table-us-00006-en] TABLE 5 Mass spectrometric of control conjugate 2 and Agent 4. Mass Mass Molecule Molecular formula Calculated Observed Control conjugate 2 C93H117Cl2N26O18S2 2019.79 2020.27 Agent 4 C77H105ClN23O16S 1674.75 1675.32
78 mg
With trifluoroacetic acid; In chloroform; at 40℃; for 16h;
(+)-JQl (90 mg, 0.20 mmol) was dissolved in 5 % TFA in chloroform (5 mL) and stirred for 16 hours at 40 C after which the solvent was evaporated. Chloroform (5 mL) was added and evaporated under vacuum, this was repeated twice to yield the product which was used without further characterization. Yield = 78 mg, 0.20 mmol h = >99 %.
In tetrahydrofuran; butan-1-ol; at 20 - 90℃; for 2h;
In a 500mL two neck round-bottomed flask equipped with a magnetic stir bar was dissolved amide 5 (3.40g, 8.13mmol) in THF (60mL) and cooled to -78C. While stirring at -78C, potassium tert-butoxide (1.0M solution in THF, 8.95mL, 8.94mmol, 1.10equiv) was added. The reaction mixture was warmed to -10C and stirred for 30min. The reaction mixture was cooled to -78C and diphenyl chlorophosphate (2.02mL, 9.76mmol) was added to the reaction mixture. The resulting mixture was warmed to -10C and stirred at this temperature for 45min. Acetylhydrazide (0.90, 12.20mmol, 1.50equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature. After 1h, 1-butanol (70mL) was added to the reaction mixture, which was heated to 90C. After 1h, all solvents were removed under reduce pressure. The residue was dissolved in CH2Cl2 and washed with saturated aq. NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain crude (+)-JQ1, which was purified by flash column chromatography on silica gel (0-100% ethyl acetate in hexanes) to afford (+)-JQ1 (3.04g, 82%) as a white solid and with a 91:9 er (determined with Supercritical Fluid Chromatography (SFC) using the CHIRALPAK AS-H column, CO2-EtOH (3:1), 210nm, tR (R-enantiomer) 1.62min, tR (S-enantiomer) 3.51min). This product was further purified by preparative SFC using a CHIRALPAK AS-H column to obtain (+)-JQ1 (S-enantiomer) with >99% ee. The spectral data of (+)-JQ1 matched with those described in the literature6 with the exception of the optical rotation. [alpha]D22 +41 (c 0.50, CHCl3), (Lit. [alpha]D22 +55 (c 0.50, CHCl3);12 (-)-JQ1: >99% ee, [alpha]D22 -39 (c 0.55, CHCl3), (Lit. [alpha]D22 -55 (c 0.50, CHCl3).6
(S)-tert-butyl 4-(3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)propyl)piperazine-1-carboxylate[ No CAS ]
(S)-tert-butyl (6-(4-(3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)propyl)piperazin-1-yl)-6-oxohexyl)carbamate[ No CAS ]
2-{4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}-N-[4-(2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl]oxy}acetamido)butyl]acetamide[ No CAS ]
(S)-N-(3-(4-(6-aminohexanoyl)piperazin-1-yl)propyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide[ No CAS ]
Hydrazide (0.015 mL, 0.45 mmol, 1.25 equiv) was added to compound 9 (158 mg, 0.36 mmol, 1 equiv) in THF. The reaction mixture was heated to 23 C and stirred for 1 h.The solvent was removed by distillation under reduced pressure, and the resulting hydrazide was used without purification. The hydrazide was dissolved in a 2: 3 volume ratio of trimethyl orthoacetate and toluene solution (6 mL, 0.06 M).The reaction mixture was heated to 120 C. After 2 h, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to give Compound 10 (14 mg, 85% yield).
(2S,4R)-1-[(2S)-2-(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide[ No CAS ]
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl)acetamide[ No CAS ]
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butyl)acetamide[ No CAS ]
(2S,4R)-N-[2-(2-{2-[2-(2-{2-[(9S)-7-(4-chloroph)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethoxy)-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2-carboxamide[ No CAS ]
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