* 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.
N-BOC-3-bromo-5-azaindole[00146] Referring now to the Scheme 1 as shown in Fig. 1 , a solution of 3.5601g(18.06 mmol) of 3-bromo-5-azaindole (2) and 0.4651 g (3.8 mmol, 21 molpercent) of dimethylaminopyridine (DMAP) in 80 ml. of THF was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 4.7769g (21.88 mmol, 1.2 eq.) of BOC2O was added to the flask at 17°C, and the resulting mixture was stirred until starting 3-bromo-5-azaindole disappeared, as monitored by TLC (generally, overnight stirring at room temperature). The resulting yellow solution was concentrated on rotavap, washed with 100 ml. of saturated sodium bicarbonate, and extracted with dichloromethane (3x80 ml_). The organic phase was dried over Na2SO4 and concentrated on rotavap to afford 6.57g of orange solid. This crude material was purified on CombiFlash using hexane/ethyl acetate as eluent to give 5.25g (97percent yield) of n-boc-3-bromo-5-azaindole (3) as a white solid.
90%
With dmap In dichloromethane for 1.33333 h;
To a mixture of Intermediate 1 (1.80 g, 9.14 mmol) in DCM (60 mL) was added di-tert- butyl dicarbonate (2.18 g, 10.0 mmol) followed by 4-dimethylaminopyridine (122 mg, 1.00 mmol). After 80 min the solution was diluted with DCM (20 mL) and washed with 0.1 M HC1 (25, 10 mL) and brine. The organic layer was dried (Na2S04), filtered and evaporated to yield the title compound as a light yellow solid (2.47 g, 90percent). MS (ESI+) m/z = 299 (M+H)+.
90%
With dmap In dichloromethane at 20℃; for 1.33333 h;
To a mixture of Intermediate 1 (1.80 g, 9.14 mmol) in DCM (60 mL) was added di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) followed by 4-dimethylaminopyridine (122 mg, 1.00 mmol). After 80 min the solution was diluted with DCM (20 mL) and washed with 0.1 M HCl (25, 10 mL) and brine. The organic layer was dried (Na2SO4), filtered and evaporated to yield the title compound as a light yellow solid (2.47 g, 90percent). MS (ESI+) m/z=299 (M+H)+.
N-BOC-<strong>[23612-36-4]3-bromo-5-azaindole</strong>[00146] Referring now to the Scheme 1 as shown in Fig. 1 , a solution of 3.5601g(18.06 mmol) of <strong>[23612-36-4]3-bromo-5-azaindole</strong> (2) and 0.4651 g (3.8 mmol, 21 mol%) of dimethylaminopyridine (DMAP) in 80 ml. of THF was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 4.7769g (21.88 mmol, 1.2 eq.) of BOC2O was added to the flask at 17C, and the resulting mixture was stirred until starting <strong>[23612-36-4]3-bromo-5-azaindole</strong> disappeared, as monitored by TLC (generally, overnight stirring at room temperature). The resulting yellow solution was concentrated on rotavap, washed with 100 ml. of saturated sodium bicarbonate, and extracted with dichloromethane (3x80 ml_). The organic phase was dried over Na2SO4 and concentrated on rotavap to afford 6.57g of orange solid. This crude material was purified on CombiFlash using hexane/ethyl acetate as eluent to give 5.25g (97% yield) of n-boc-<strong>[23612-36-4]3-bromo-5-azaindole</strong> (3) as a white solid.
90%
With dmap; In dichloromethane; for 1.33333h;
To a mixture of Intermediate 1 (1.80 g, 9.14 mmol) in DCM (60 mL) was added di-tert- butyl dicarbonate (2.18 g, 10.0 mmol) followed by 4-dimethylaminopyridine (122 mg, 1.00 mmol). After 80 min the solution was diluted with DCM (20 mL) and washed with 0.1 M HC1 (25, 10 mL) and brine. The organic layer was dried (Na2S04), filtered and evaporated to yield the title compound as a light yellow solid (2.47 g, 90%). MS (ESI+) m/z = 299 (M+H)+.
90%
With dmap; In dichloromethane; at 20℃; for 1.33333h;
To a mixture of Intermediate 1 (1.80 g, 9.14 mmol) in DCM (60 mL) was added di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) followed by 4-dimethylaminopyridine (122 mg, 1.00 mmol). After 80 min the solution was diluted with DCM (20 mL) and washed with 0.1 M HCl (25, 10 mL) and brine. The organic layer was dried (Na2SO4), filtered and evaporated to yield the title compound as a light yellow solid (2.47 g, 90%). MS (ESI+) m/z=299 (M+H)+.
tetraethyl-5-azaindol-3-yl-ethyl-bisphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
Example 3Tetraethyl- 5-azaindol-3-yl-ethyl-bisphosphonate[00147] Referring now to the Scheme 1 as shown in Fig. 1 , a solution of 2.9138g(9.805 mmol) of N-boc-3-bromo-5-azaindole in 50 ml. of anhydrous THF was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling dry ice/acetone bath. A total of 4.3 ml. (10.75 mmol, 1.1 eq.) of 2.5Lambda/ solution of n-butyl lithium in hexane was slowly added to N-boc-3-bromo-5- azaindole with the rate to maintain the reaction temperature below -73C. The resulting orange-colored solution stirred at -73C for 30 min, and a total of 2.9485g (9.82 mmol, 1 eq.) of vinyl bisphosphonate, tetraethyl ethane-1 ,1-bisphosphonate (prepared according to the procedures given in J. Org. Chem. 1986, 51 , 3488-3490, incorporated herein by reference in its entirety) was slowly added and after stirring at -73C for 20 min the resulting mixture was allowed to warm to room temperature. The reaction was quenched with 100 ml. of cold water, and the products extracted with ethyl acetate (3x50 ml_). [00148] The organic phase was dried over Na2SO4 and then concentrated on rotavap to give 5.67g of red oil. This crude material was purified on CombiFlash using ethyl acetate/methanol as eluent to give 3.6g (71% yield) of a mixture (80:20 by NMR) of two isomers, tetraethyl-n-boc-(5-azaindol-3-yl)-ethyl-bisphosphonate and tetraethyl-n- boc-(5-azaindol-2-yl)-ethyl-bisphosphonate. The isomers were inseparable by chromatography failed due to close Rf-values (Rf = 0.17 in EtOAc/MeOH=9:1 ). [00149] To achieve acceptable separation, the obtained mixture of isomers (3.6 g) was stirred for two days with 5 ml. of TFA in a mixture of 50 ml. of acetonitrile containing 0.1 % TFA and 20 ml. of water containing 0.1 % TFA (mobile phases for HPLC). After two days complete deprotection was observed by HPLC. The volume of the reaction mixture was decreased to 50 mL by concentration on rotavap, and the clear solution was purified by preparative HPLC (four runs) to separate the azaindol-2-yl from the azaindol 3-yl. The purity of the obtained fractions was monitored by 31P NMR. The pure fractions were combined, concentrated on rotavap, and the obtained clear oil was washed with 50 mL of saturated sodium bicarbonate. The organic material was extracted with dichloromethane (3x30 mL), and the combined organic phases were dried over sodium sulfate and concentrated on rotavap to afford 1.14 g (39% yield) of tetraethyl- 5-azaindol- 3-yl-ethyl-bisphosphonate as a white solid.
Example 3Tetraethyl- 5-azaindol-3-yl-ethyl-bisphosphonate[00147] Referring now to the Scheme 1 as shown in Fig. 1 , a solution of 2.9138g(9.805 mmol) of N-boc-3-bromo-5-azaindole in 50 ml. of anhydrous THF was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling dry ice/acetone bath. A total of 4.3 ml. (10.75 mmol, 1.1 eq.) of 2.5Lambda/ solution of n-butyl lithium in hexane was slowly added to N-boc-3-bromo-5- azaindole with the rate to maintain the reaction temperature below -73C. The resulting orange-colored solution stirred at -73C for 30 min, and a total of 2.9485g (9.82 mmol, 1 eq.) of vinyl bisphosphonate, tetraethyl ethane-1 ,1-bisphosphonate (prepared according to the procedures given in J. Org. Chem. 1986, 51 , 3488-3490, incorporated herein by reference in its entirety) was slowly added and after stirring at -73C for 20 min the resulting mixture was allowed to warm to room temperature. The reaction was quenched with 100 ml. of cold water, and the products extracted with ethyl acetate (3x50 ml_). [00148] The organic phase was dried over Na2SO4 and then concentrated on rotavap to give 5.67g of red oil. This crude material was purified on CombiFlash using ethyl acetate/methanol as eluent to give 3.6g (71% yield) of a mixture (80:20 by NMR) of two isomers, tetraethyl-n-boc-(5-azaindol-3-yl)-ethyl-bisphosphonate and tetraethyl-n- boc-(5-azaindol-2-yl)-ethyl-bisphosphonate. The isomers were inseparable by chromatography failed due to close Rf-values (Rf = 0.17 in EtOAc/MeOH=9:1 ). [00149] To achieve acceptable separation, the obtained mixture of isomers (3.6 g) was stirred for two days with 5 ml. of TFA in a mixture of 50 ml. of acetonitrile containing 0.1 % TFA and 20 ml. of water containing 0.1 % TFA (mobile phases for HPLC). After two days complete deprotection was observed by HPLC. The volume of the reaction mixture was decreased to 50 mL by concentration on rotavap, and the clear solution was purified by preparative HPLC (four runs) to separate the azaindol-2-yl from the azaindol 3-yl. The purity of the obtained fractions was monitored by 31P NMR. The pure fractions were combined, concentrated on rotavap, and the obtained clear oil was washed with 50 mL of saturated sodium bicarbonate. The organic material was extracted with dichloromethane (3x30 mL), and the combined organic phases were dried over sodium sulfate and concentrated on rotavap to afford 1.14 g (39% yield) of tetraethyl- 5-azaindol- 3-yl-ethyl-bisphosphonate as a white solid.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 1.33333h;
Intermediate 2 (33.0 mg, 0.10 mmol) was mixed with 80% aqueous dimethoxyethane (1 mL), 4-chlorophenylboronic acid (23.0 mg, 0.15 mmol) and K2CO3 (35.0 mg, 0.25 mmol). Tetrakis-(triphenylphosphine)palladium(0) (6.00 mg, 0.005 mmol) was added and the mixture was stirred at 80 C for 80 min. After cooling, water (0.8 mL) and EtOAc (8 mL) were added. The mixture was centrifuged and the organic layer was separated. Flash chromatography (1 :3 EtO Ac/toluene) gave the title compound (21 mg, 64%). HRMS (ESI+) calcd for Ci8H17ClN202 328.0979, found 328.0980.
64%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 1.33333h;
Intermediate 2 (33.0 mg, 0.10 mmol) was mixed with 80% aqueous dimethoxyethane (1 mL), 4-chlorophenylboronic acid (23.0 mg, 0.15 mmol) and K2CO3 (35.0 mg, 0.25 mmol). Tetrakis-(triphenylphosphine)palladium(0) (6.00 mg, 0.005 mmol) was added and the mixture was stirred at 80 C. for 80 min. After cooling, water (0.8 mL) and EtOAc (8 mL) were added. The mixture was centrifuged and the organic layer was separated. Flash chromatography (1:3 EtOAc/toluene) gave the title compound (21 mg, 64%). HRMS (ESI+) calcd for C is H17ClN2O2 328.0979, found 328.0980.