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CAS No. : | 1357576-48-7 | MDL No. : | MFCD31657439 |
Formula : | C45H48ClF3N4O7S3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 945.53 | Pubchem ID : | - |
Synonyms : |
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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: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: chlorosulfonic acid / 18 h / 125 °C 1.2: 1.5 h / -65 - 0 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 50 °C 3.1: diisobutylaluminium hydride / dichloromethane; n-heptane / 3 h / -78 °C 3.2: -78 - 25 °C 4.1: sodium tris(acetoxy)borohydride / 1,2-dichloro-ethane / 11.5 h / Darkness 5.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h 6.1: hydrogenchloride / 1,4-dioxane; methanol / 0 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; at -10℃; for 0.666667h;Inert atmosphere; | Compound A (25.50g, 2.70 x 1 02 mol) and TDA (4.81 g, 3.64 x 1 02 mol, 1.35 equiv.)were charged into a 3-neck reaction vessel fitted with an internal temperature probe andpressure equalizing dropping funnel under an atmosphere of N2. DCM (255 mL, 10 vol.) wasintroduced, and the ensuing suspension was cooled to -10C. 0.29M TEA in DCM, (100 mL, 3.77 x 1 Q-2 mol, 1 .4 equiv.) was introduced over a 40 minute period whilst maintaining thetemperature at -10C. Reaction in-process controls (IPC?s) were taken hourly. The reaction wasdeemed complete when Compound A was <10% area by HPLC (typically 4.5 h after the end ofaddition). The reaction mixture was diluted with DCM (1 .66 L, 65 vol.) and washed three timeswith aq. phosphate buffered saline (PBS) solution (1.02 L, 40 vol.). The combined organicextracts were dried over Mg504 (100 g, 5% wlv), affording a pale yellow solid afterconcentration in vacuo (0.2 bar, 25C) overnight (typically 24.5 g, 85% yield, 86.83% by HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 7 Preparation of DGA-Compound A To a magnetically stirred suspension of Compound A (77 mg, 81 .5 mol) in DCM (5 mL)at room temperature was added diglycolic anhydride (9.6 mg, 81 .5 mol) and DIPEA (36 L,200 mol). The suspension dissolved quickly and the mixture was left to stir at roomtemperature overnight. Additional diglycolic anhydride was added over the following 24 hoursuntil the reaction was judged >80% complete by H PLC. The volatiles were then removed invacuo and the residue purified by preparative HPLC (BEH 300 Waters XBridge C18, 5 pM, 30 x150 mm, 60-80% ACN/water (5-40 mm), 0.1% TFA, RT = 22 mm) providing 76 mg (87%) ofproduct as awhite solid. LCMS (C18, gradient: 50-60% ACN/H20 (1-10 mm), 60% ACN (10-11mm), 60-50% ACN (11-13 mm), 50% ACN (13-15 mm), 0.1% formic acid, 0.4 mL/min, Rf (mm) =5.93. ESI (+ve) observed [M + H] = 1061. Calculated for C49H52C1F3N4011S3 = 1060.24 Da.1H-NMR (300MHz, CD3OD) 6 (ppm): 0.86-1.04 (m, 1H), 1.08-1.32 (m, 2H), 1.70-1.90 (m, 1H),1.97-2.08 (m, 1H), 2.08-2.20 (m, 1H), 2.22-2.38 (m, 1H), 2.65 (t, J = 12.3 Hz, 1H), 2.77 (t, J =12.6 Hz, 1H), 2.92 (s, 3H), 3.15-3.29 (m, 2H), 3.36-3.42 (m, 2H), 3.46-3.54 (m, 2H), 3.73 (d, J =12.6 Hz, 1H), 3.90 (d, J = 11.7Hz, 1H), 3.99-4.15 (m, 1H), 4.20 (s, 2H), 4.28 (s, 2H), 4.42 (j, J =8.1 Hz, 1 H), 4.45-4.54 (m, 2H), 6.86 (d, J = 9.3Hz, 2H), 6.92 (d, J = 9.6 Hz, 1 H), 7.01 (d, J =9.3Hz, 1H), 7.10-7.26 (m, 4H), 7.26-7.47 (m, 7H), 7.59 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 9.0 Hz,2H), 8.08 (dd, J = 9.0, 2.1 Hz, 1 H), 8.31 (d, J = 2.1 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; | 9 Alternative method of preparation Compound A (28.00 g, 2.96 x 102 mol) and 4-methylmorpholine-2,6-dione (7.24 g, 5.33x 10-2 mol., 1 .80 equiv.) were charged into a 3-neck reaction vessel with an internaltemperature probe and pressure equalizing dropping funnel, under an atmosphere of N2. DCM(250 mL, 9 vol.) was introduced, and the ensuing suspension was cooled to 0 °C. TEA (6.25mL,4.44x 102mo1., 1.Sequiv.) in DCM (50 mL, 1.8 vol.) was added drop-wise overalOminute period whilst maintaining the temperature at 0 °C. Reaction in process controls weretaken hourly. The reaction was deemed complete when Compound A is <10% by peak area(typically 4.5 h after the end of addition). The reaction mixture is diluted with DCM (1 .40 L, 50vol.) and washed twice with 1 .6 M aq. Na2CO3 (1 .60 L, 50 vol.). The organic layer was driedover MgSO4 (90 g, 5% wlv), filtered through a sintered glass funnel and washed with DCM (100mL, 5 vol.) affording an off-white solid after concentration in vacuo (0.2 bar, 30°C) (33.07 g, 95%yield, 90.6% by HPLC). |
95% | With 4-methyl-morpholine; triethylamine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; | 1.2.a (a) Preparation of MIDA-Compound A Compound A (28.00 g, 2.96 x 10 2 mol) and 4-methylmorpholine-2,6-dione (7.24 g, 5.33 x 10-2 mol., 1 .80 equiv.) were charged into a 3-neck reaction vessel with an internal temperature probe and pressure equalizing dropping funnel, under an atmosphere of N2. DCM (250 ml_, 9 vol.) was introduced, and the ensuing suspension was cooled to 0 °C. TEA (6.25 ml_, 4.44 x 10 2 mol., 1 .5 equiv.) in DCM (50 ml_, 1 .8 vol.) was added drop-wise over a 10 minute period whilst maintaining the temperature at 0 °C. Reaction in process controls were taken hourly. The reaction was deemed complete when Compound A is <10% by peak area (typically 4.5 h after the end of addition). The reaction mixture is diluted with DCM (1 .40 L, 50 vol.) and washed twice with 1 .6 M aq. Na2C03 (1 .60 L, 50 vol.). The organic layer was dried over MgS04 (90 g, 5% w/v), filtered through a sintered glass funnel and washed with DCM (100 ml_, 5 vol.) affording an off-white solid after concentration in vacuo (0.2 bar, 30°C) (33.07 g, 95% yield, 90.6% by HPLC). |
84% | With 4-methyl-morpholine; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 2.a a) Preparation of MIDA-Compound A To a magnetically stirred suspension of Compound A (200 mg, 0.21 mmol) in DCM (5 ml.) at room temperature was added and DIPEA (24 pL, 0.14 mmol), NMM (72 mI_, 0.66 mmol) and 4-methylmorpholine-2,6-dione (33 mg, 0.26 mmol). The suspension dissolved quickly and the mixture was left to stir at room temperature overnight. Additional 4-methylmorpholine-2,6- dione was added over the following 24 hours until the reaction was judged >80% complete by HPLC. The volatiles were then removed in vacuo and the residue purified by preparative HPLC (BEH 300 Waters XBridge C18, 5 mM, 30 x 150 mm, 50-70% ACN/water (5-40 min), 0.1 % TFA, RT = 23 min) providing 190 mg (84%) of product as a white solid. LCMS (C18, gradient: 50- 60% ACN/H2O (1 -10 min), 60% ACN (10-1 1 min), 60-50% ACN (1 1-13 min), 50% ACN (13-15 min), 0.1 % formic acid, 0.4 mL/min, Rf (min) = 2.55. ESI (+ve) observed [M + H]+ = 1074. Calculated for C50H55CIF3N5O10S3 = 1073.28 Da. 1 H-NMR (300MHz, CD3OD) d (ppm): 0.86-1 .07 (m, 1 H), 1 .08-1.37 (m, 2H), 1 .72-1 .88 (m, 1 H), 1 .96-2.09 (m, 1 H), 2.10-2.24 (m, 1 H), 2.24-2.38 (m, 1 H), 2.66 (t, J = 12.3 Hz, 1 H), 2.79 (t, J = 12.6 Hz, 1 H), 2.92 (s, 3H), 3.00 (s, 3H), 3.14-3.28 (m, 2H), 3.33-3.43 (m, 2H), 3.47-3.57 (m, 2H), 3.72 (d, J = 12.0 Hz, 1 H), 3.89 (d, J = 12.6 Hz, 1 H), 4.03-4.15 (m, 1 H), 4.06 (s, 2H), 4.19 (s, 2H), 4.43 (d, J = 8.1 Hz, 1 H), 4.54-4.64 (m, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.6 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 1 H), 7.09-7.25 (m, 4H), 7.26-7.47 (m, 8H), 7.61 (d, J = 8.1 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 2H), 8.07 (dd, J = 9.3, 2.1 Hz, 1 H), 8.31 (d, J = 2.1 Hz, 1 H). |