* 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.
(D) 5,7-dichloropyrido[4,3-.pound.>]pyrazi neA mixture of the solution of 2,6-dichloropyridine-3,4-diamine (7.85 g, 0.044 mol) in ethanol and 40percent glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83percent yield).
83%
Reflux
(D) 5,7-dichloropyrido[4,3-.pound.>]pyrazi ne[084] A mixture of the solution of 2,6-dichloropyridine-3,4-diamine (7.85 g, 0.044 mol) in ethanol and 40percent glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83percent yield).
83%
Reflux
A mixture of the solution of 2,6-dichloropyridine-3,4-diamine (7.85 g, 0.044 mol) in ethanol and 40percent glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83percent yield).
8.17 g
for 1 h; Reflux
Intermediate 4: 5,7-Dichloropyrido[3,4-b]pyrazine 2,6-dichloro-3,4-pyridinediamine (10 g, 56.2 mmol) was suspended in tert-butanol (50 ml) and treated with glyoxal (10.27 mL, 225 mmol). The resulting solution was allowed to stir at reflux for 1 h. The hot solution was poured onto water (200 ml) and allowed to stir for 20 min. The resulting precipitate was removed by filtration and washed with water (100 ml). The resulting brown solid was taken up in DCM, filtered and loaded onto a 2 inch silica plug on a sinter funnel and eluted with EtOAc (2*100 ml). The combined eluents were concentrated to give the title compound as a deep grey solid (8.17 g). LCMS (Method B): Rt=0.81 min, MH+=199.86, 201.42
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 0.666667 h; Microwave irradiation
Intermediate 22: 1,1-Dimethylethyl (2R)-2-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-4-morpholinecarboxylate 1,1-dimethylethyl (2R)-2-(aminomethyl)-4-morpholinecarboxylate (for preparation see: J. Medicinal Chemistry, 2009, 52 (15), 4810-4819) (6 g, 27.7 mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (60 mL) and to this was added DIPEA (7.27 mL, 41.6 mmol) and 5,7-dichloropyrido[3,4-b]pyrazine (5.55 g, 27.7 mmol). This was split between 4 large microwave vials and each was heated at 130° C. for 30 min. They were monitored by LCMS and were given a further 10 min at 130° C. The reaction mixtures were partitioned between ethyl acetate (700 ml) and diluted aqueous ammonium chloride (1 litre). The aqueous was reextracted with ethyl acetate (300 ml) and the combined organics were washed with aqueous ammonium chloride (500 ml), dried over sodium sulfate and concentrated in vacuo to yield a crude brown oil. It was dissolved in DCM and passed through silica (70 g) eluting with DCM (6*40 ml) then 5percent ethyl acetate in DCM (2*40 ml), 10percent ethyl acetate in DCM (5*40 ml) then 15percent ethyl acetate in DCM (2*40 ml) then 20percent ethyl acetate in DCM (2*40 ml). Appropriate fractions were combined and concentrated in vacuo to yield: N8231-100-2, orange-yellow slightly gummy solid, 7.7 g LCMS (Method B): Rt=1.17 min, MH+ 380
(D) 5,7-dichloropyrido[4,3-£>]pyrazi neA mixture of the solution of <strong>[101079-63-4]2,6-dichloropyridine-3,4-diamine</strong> (7.85 g, 0.044 mol) in ethanol and 40% glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83% yield).
83%
In ethanol; water;Reflux;
(D) 5,7-dichloropyrido[4,3-£>]pyrazi ne[084] A mixture of the solution of <strong>[101079-63-4]2,6-dichloropyridine-3,4-diamine</strong> (7.85 g, 0.044 mol) in ethanol and 40% glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83% yield).
83%
In ethanol; water;Reflux;
A mixture of the solution of <strong>[101079-63-4]2,6-dichloropyridine-3,4-diamine</strong> (7.85 g, 0.044 mol) in ethanol and 40% glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83% yield).
In tert-butyl alcohol; for 1h;Reflux;
Intermediate 4: 5,7-Dichloropyridor3,4-blpyrazine; <strong>[101079-63-4]2,6-dichloro-3,4-pyridinediamine</strong> (10g, 56.2mmol) was suspended in tert-butanol (50ml) and treated with glyoxal (10.27mL, 225mmol). The resulting solution was allowed to stir at reflux for 1 h. The hot solution was poured onto water (200ml) and allowed to stir for 20min. The resulting precipitate was removed by filtration and washed with water (100ml). The resulting brown solid was taken up in DCM, filtered and loaded onto a 2 inch silica plug on a sinter funnel and eluted with EtOAc (2x100ml). The combined eluents were concentrated to give the title compound as a deep grey solid (8.17g).LCMS (Method B): Rt = 0.81 min, MH+ = 199.86, 201.42
8.17 g
In tert-butyl alcohol; for 1h;Reflux;
Intermediate 4: 5,7-Dichloropyrido[3,4-b]pyrazine <strong>[101079-63-4]2,6-dichloro-3,4-pyridinediamine</strong> (10 g, 56.2 mmol) was suspended in tert-butanol (50 ml) and treated with glyoxal (10.27 mL, 225 mmol). The resulting solution was allowed to stir at reflux for 1 h. The hot solution was poured onto water (200 ml) and allowed to stir for 20 min. The resulting precipitate was removed by filtration and washed with water (100 ml). The resulting brown solid was taken up in DCM, filtered and loaded onto a 2 inch silica plug on a sinter funnel and eluted with EtOAc (2*100 ml). The combined eluents were concentrated to give the title compound as a deep grey solid (8.17 g). LCMS (Method B): Rt=0.81 min, MH+=199.86, 201.42
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;microwave irradiation;
Intermediate 5: 1 ,1-Dimethylethyl (3 ~)-3-fr(7-chloropyridor3,4-blpyrazin-5- yl)amino1methviyi-piperidinecarboxylate; 5,7-dichloropyrido[3,4-b]pyrazine (1g, 5.00mmol) was taken up in N-Methyl-2- pyrrolidone (NMP) (10ml) and treated with 1 , 1-dimethylethyl (3f~)-3-(aminomethyl)-1- piperidinecarboxylate (1.179g, 5.50mmol) (Apollo Scientific Ltd) and diisopropylethylamine (1.310ml, 7.50mmol). The reaction was irradiated in a Biotage microwave at 130C for 30min. The reaction was partitioned between EtOAc (100ml) and water (100ml). The organic layer was washed with brine (100ml), dried using a hydrophobic frit and concentrated to give a black solid. This solid was purified on silica (50g) and eluted with a 10-40% EtOAc/cyclohexane gradient. The appropriate fractions were combined and concentrated to give the title compound as a deep orange solid (1.542g).LCMS (Method B): Rt = 1.28min, MH+ = 377.92
1.542 g
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;Microwave irradiation;
Intermediate 5: 1,1-Dimethylethyl (3R)-3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-1-piperidinecarboxylate 5,7-dichloropyrido[3,4-b]pyrazine (1 g, 5.00 mmol) was taken up in N-Methyl-2-pyrrolidone (NMP) (10 ml) and treated with <strong>[140645-23-4]1,1-dimethylethyl (3R)-3-(aminomethyl)-1-piperidinecarboxylate</strong> (1.179 g, 5.50 mmol) (Apollo Scientific Ltd) and diisopropylethylamine (1.310 ml, 7.50 mmol). The reaction was irradiated in a Biotage microwave at 130 C. for 30 min. The reaction was partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried using a hydrophobic frit and concentrated to give a black solid. This solid was purified on silica (50 g) and eluted with a 10-40% EtOAc/cyclohexane gradient. The appropriate fractions were combined and concentrated to give the title compound as a deep orange solid (1.542 g). LCMS (Method B): Rt=1.28 min, MH+=377.92
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;microwave irradiation; sealed tube;
Intermediate 32: 1 ,1-Dimethylethyl {4-r(7-chloropyridor3,4-blpyrazin-5- vDaminolbutvDcarbamate; To <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (650mg, 3.25mmol) was added 1 , 1- dimethylethyl (4-aminobutyl)carbamate (0.622ml, 3.25mmol) (Fluka) and diisopropylethylamine (0.851 ml, 4.87mmol). To the mixture was added N-methyl-2- pyrrolidone (NMP) (10ml). The microwave vial was sealed and heated to 130C for 30min. The reaction mixture was partitioned between water (70ml) and ethyl acetate (70ml) and then separated. The aqueous layer was extracted with ethyl acetate (2x50ml). The combined organics were passed through a phase separation cartridge and reduced in vacuo. The residue was dissolved in DCM and loaded onto a silica cartridge (50g) and purified via SP4 using a 15-75% EtOAc in cyclohexane gradient. The appropriate fractions were combined and concentrated to give the title compound as a yellow film (1.01g).LCMS (Method C): Rt = 1.11 min, MH+ = 352.0
1.01 g
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;Microwave irradiation; Sealed tube;
Intermediate 32: 1,1-Dimethylethyl {4-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]butyl}carbamate To <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (650 mg, 3.25 mmol) was added 1,1-dimethylethyl (4-aminobutyl)carbamate (0.622 ml, 3.25 mmol) (Fluka) and diisopropylethylamine (0.851 ml, 4.87 mmol). To the mixture was added N-methyl-2-pyrrolidone (NMP) (10 ml). The microwave vial was sealed and heated to 130 C. for 30 min. The reaction mixture was partitioned between water (70 ml) and ethyl acetate (70 ml) and then separated. The aqueous layer was extracted with ethyl acetate (2*50 ml). The combined organics were passed through a phase separation cartridge and reduced in vacuo. The residue was dissolved in DCM and loaded onto a silica cartridge (50 g) and purified via SP4 using a 15-75% EtOAc in cyclohexane gradient. The appropriate fractions were combined and concentrated to give the title compound as a yellow film (1.01 g). LCMS (Method C): Rt=1.11 min, MH+=352.0
Intermediate 18: 1,1-Dimethylethyl (3S)-3-{r(7-chloropyridor3,4-6lpyrazin-5- yl)oxy1methyl)-1-piperidinecarboxylate; 1 , 1-Dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (129mg, 0.600mmol) (Apollo Scientific Limited) was taken up in N,N-dimethylformamide (DMF) (3ml), treated with sodium hydride (23.99mg, 0.600mmol) and allowed to stir at room temperature for 20min, a yellow solution resulted. 5,7-dichloropyrido[3,4- £>]pyrazine (100mg, 0.500mmol) was added and the reaction was allowed to stir at room temperature for a further 1 h. The reaction was partitioned between EtOAc (50ml) and NH4CI (50ml). The organic layer was dried using a hydrophobic frit and concentrated to give a brown oil. This oil was purified on silica (25g) using a 0-40% EtOAc/cyclohexane gradient. The appropriate fractions were summed and concentrated to give the title compound as a yellow gum (91 mg).LCMS (Method B): Rt = 1.26min, MH+ = 378.88
91 mg
Intermediate 18: 1,1-Dimethylethyl (3S)-3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)oxy]methyl}-1-piperidinecarboxylate 1,1-Dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (129 mg, 0.600 mmol) (Apollo Scientific Limited) was taken up in N,N-dimethylformamide (DMF) (3 ml), treated with sodium hydride (23.99 mg, 0.600 mmol) and allowed to stir at room temperature for 20 min, a yellow solution resulted. <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (100 mg, 0.500 mmol) was added and the reaction was allowed to stir at room temperature for a further 1 h. The reaction was partitioned between EtOAc (50 ml) and NH4Cl (50 ml). The organic layer was dried using a hydrophobic frit and concentrated to give a brown oil. This oil was purified on silica (25 g) using a 0-40% EtOAc/cyclohexane gradient. The appropriate fractions were summed and concentrated to give the title compound as a yellow gum (91 mg). LCMS (Method B): Rt=1.26 min, MH+=378.88
Intermediate 20: 1 ,1-Dimethylethyl (2S)-2-{r(7-chloropyridor3,4-6lpyrazin-5- yl)oxy1methyl)-4-morpholinecarboxylate; 1 , 1-Dimethylethyl (2S)-2-(hydroxymethyl)-4-morpholinecarboxylate (Preparation reference: WO 2009/071658) (586mg, 2.70mmol) was dissolved in N,N- Dimethylformamide (7ml_) and cooled in an ice bath to 5C under a nitrogen atmosphere. Sodium hydride 60% in mineral oil (162mg, 4.05mmol) was added portionwise over 15min. 5,7-dichloropyrido[3,4-b]pyrazine (647mg, 3.24mmol) was then added portionwise and the mixture stirred at 5C for 35min and quenched by addition of saturated aqueous ammonium chloride solution (20ml_). The solution was partitioned between ethyl acetate and water. The aqueous was re-extracted with ethyl acetate and the combined organic layers were washed with water, separated using a phase separation cartridge and the solvent removed to give a brown solid. The crude residue was dissolved in DCM and purified by silica chromatography eluting with a 12-62% ethyl acetate in petroleum ether gradient. The appropriate fractions were combined and the solvent was evaporated to give the title compound as a brown solid (917mg).LCMS (Method B): Rt = 1.12min, MH+ = 380.9
917 mg
Intermediate 20: 1,1-Dimethylethyl (2S)-2-[(7-chloropyrido[3,4-b]pyrazin-5-yl)oxy]methyl}-4-morpholinecarboxylate 1,1-Dimethylethyl (2S)-2-(hydroxymethyl)-4-morpholinecarboxylate (Preparation reference: WO 2009/071658) (586 mg, 2.70 mmol) was dissolved in N,N-Dimethylformamide (7 mL) and cooled in an ice bath to 5 C. under a nitrogen atmosphere. Sodium hydride 60% in mineral oil (162 mg, 4.05 mmol) was added portionwise over 15 min. 5,7-dichloropyrido[3,4-b]pyrazine (647 mg, 3.24 mmol) was then added portionwise and the mixture stirred at 5 C. for 35 min and quenched by addition of saturated aqueous ammonium chloride solution (20 mL). The solution was partitioned between ethyl acetate and water. The aqueous was re-extracted with ethyl acetate and the combined organic layers were washed with water, separated using a phase separation cartridge and the solvent removed to give a brown solid. The crude residue was dissolved in DCM and purified by silica chromatography eluting with a 12-62% ethyl acetate in petroleum ether gradient. The appropriate fractions were combined and the solvent was evaporated to give the title compound as a brown solid (917 mg). LCMS (Method B): Rt=1.12 min, MH+=380.9
1.83 g
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 72h;
To a mixture of 5,7-dichloropyrido[4,3-b]pyrazine (2.3 g, 11,51 mmol) and potassium carbonate (4.76 g, 34.52 mmol) in DMF (100 ml) was added <strong>[135065-76-8](S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate</strong> (5.0 g, 23.01 mmol), then the mixture was stirred at 40 C for 72 hours. This solution was poured into water and extracted with EA. The combined organic phase was washed with brine, dried and purified by silicagel chromatography, eluting with MeOH /H2O=1:10~10:1, to give 1.83 g title compund.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;
Intermediate 33: 1 ,1-Dimethylethyl-2-{r(7-chloropyridor3,4-/3lpyrazin-5- yl)amino1methylV4-morpholinecarboxylate; 1 , 1-Dimethylethyl-2-(aminomethyl)-4-morpholinecarboxylate (60mg, 0.28mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (1 ml_) and to this was added DIPEA (0.07ml_, 0.38mmol) and <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (50mg, 0.25mmol). This was heated at 130C for 30min. The reaction mixtures were partitioned between ethyl acetate (50ml) and water (50m L) and the organic layer washed with water (50m L), dried over a hydrophobic frit and concentrated in vacuo to yield an orange gum. It was dissolved in DCM and passed through silica (10g) eluting with a 10-40% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a yellow solid, 91 mg.LCMS (Method B): Rt = 1.17min, MH+ 380
91 mg
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;
Intermediate 33: 1,1-Dimethylethyl-2-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-4-morpholinecarboxylate 1,1-Dimethylethyl-2-(aminomethyl)-4-morpholinecarboxylate (60 mg, 0.28 mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (1 mL) and to this was added DIPEA (0.07 mL, 0.38 mmol) and <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (50 mg, 0.25 mmol). This was heated at 130 C. for 30 min. The reaction mixtures were partitioned between ethyl acetate (50 ml) and water (50 mL) and the organic layer washed with water (50 mL), dried over a hydrophobic frit and concentrated in vacuo to yield an orange gum. It was dissolved in DCM and passed through silica (10 g) eluting with a 10-40% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a yellow solid, 91 mg. LCMS (Method B): Rt=1.17 min, MH+ 380
Intermediate 31 : 1 ,1-Dimethylethyl 3-r2-(7-chloropyridor3,4-fllpyrazin-5- yl)ethyl1-1 -piperidinecarboxylate; 9-Borabicyclo[3.3.1]nonane solution (9-BBN) (9.47ml_, 4.73mmol, 0.5M in THF) (Aldrich) was added to 1 , 1-dimethylethyl 3-ethenyl-1-piperidinecarboxylate (1 g, 4.73mmol) in THF (30ml) and the mixture was heated at reflux under nitrogen for 2h. The reaction was cooled and 5,7-dichloropyrido[3,4-£>]pyrazine (0.947g, 4.73mmol), 1 , T-bis(diphenylphosphino)ferrocenedichloro palladium (II) (0.104g, 0.142mmol), potassium carbonate (1.308g, 9.47mmol), Nu,Nu-dimethylformamide (DMF) (30 ml) and water (4ml) were added and the solution was heated at 80C for 3h. The mixture was evaporated in vacuo, diluted with water (50ml) and extracted with ether (2 x 50ml). The combined organics were washed with water (50ml), dried and evaporated to give a brown oil. The impure product was purified by chromatography (330g silica column) eluting with a 0-80% EtOAc/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as a colourless gum (1.31g). LCMS (Method B): Rt = 1.35min, MH+ 377
1.31 g
Intermediate 31: 1,1-Dimethylethyl 3-[2-(7-chloropyrido[3,4-b]pyrazin-5-yl)ethyl]-1-piperidinecarboxylate 9-Borabicyclo[3.3.1]nonane solution (9-BBN) (9.47 mL, 4.73 mmol, 0.5M in THF) (Aldrich) was added to 1,1-dimethylethyl 3-ethenyl-1-piperidinecarboxylate (1 g, 4.73 mmol) in THF (30 ml) and the mixture was heated at reflux under nitrogen for 2 h. The reaction was cooled and <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (0.947 g, 4.73 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium (II) (0.104 g, 0.142 mmol), potassium carbonate (1.308 g, 9.47 mmol), N,N-dimethylformamide (DMF) (30 ml) and water (4 ml) were added and the solution was heated at 80 C. for 3 h. The mixture was evaporated in vacuo, diluted with water (50 ml) and extracted with ether (2*50 ml). The combined organics were washed with water (50 ml), dried and evaporated to give a brown oil. The impure product was purified by chromatography (330 g silica column) eluting with a 0-80% EtOAc/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as a colourless gum (1.31 g). LCMS (Method B): Rt=1.35 min, MH+ 377
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.666667h;microwave irradiation;
Intermediate 22: 1 ,1-Dimethylethyl (2/~)-2-{r(7-chloropyridor3,4-6lpyrazin-5- yl)amino1methylV4-morpholinecarboxylate; 1 , 1-dimethylethyl (2f~)-2-(aminomethyl)-4-morpholinecarboxylate (for preparation see: J. Medicinal Chemistry, 2009, 52 (15), 4810-4819) (6g, 27.7mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (60ml_) and to this was added DIPEA (7.27ml_, 41.6mmol) and <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (5.55g, 27.7mmol). This was split between 4 large microwave vials and each was heated at 130C for 30min. They were monitored by LCMS and were given a further 10min at 130C. The reaction mixtures were partitioned between ethyl acetate (700ml) and diluted aqueous ammonium chloride (1 litre). The aqueous was reextracted with ethyl acetate (300ml) and the combined organics were washed with aqueous ammonium chloride (500ml), dried over sodium sulfate and concentrated in vacuo to yield a crude brown oil. It was dissolved in DCM and passed through silica (70g) eluting with DCM (6 X 40ml) then 5% ethyl acetate in DCM (2 X 40ml), 10% ethyl acetate in DCM (5 X 40ml) then 15% ethyl acetate in DCM (2 X 40ml) then 20%ethyl acetate in DCM (2 X 40ml). Appropriate fractions were combined and concentrated in vacuo to yield: N8231-100-2, orange-yellow slightly gummy solid, 7.7gLCMS (Method B): Rt = 1.17min, MH+ 380
7.7 g
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.666667h;Microwave irradiation;
Intermediate 22: 1,1-Dimethylethyl (2R)-2-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-4-morpholinecarboxylate 1,1-dimethylethyl (2R)-2-(aminomethyl)-4-morpholinecarboxylate (for preparation see: J. Medicinal Chemistry, 2009, 52 (15), 4810-4819) (6 g, 27.7 mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (60 mL) and to this was added DIPEA (7.27 mL, 41.6 mmol) and <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (5.55 g, 27.7 mmol). This was split between 4 large microwave vials and each was heated at 130 C. for 30 min. They were monitored by LCMS and were given a further 10 min at 130 C. The reaction mixtures were partitioned between ethyl acetate (700 ml) and diluted aqueous ammonium chloride (1 litre). The aqueous was reextracted with ethyl acetate (300 ml) and the combined organics were washed with aqueous ammonium chloride (500 ml), dried over sodium sulfate and concentrated in vacuo to yield a crude brown oil. It was dissolved in DCM and passed through silica (70 g) eluting with DCM (6*40 ml) then 5% ethyl acetate in DCM (2*40 ml), 10% ethyl acetate in DCM (5*40 ml) then 15% ethyl acetate in DCM (2*40 ml) then 20% ethyl acetate in DCM (2*40 ml). Appropriate fractions were combined and concentrated in vacuo to yield: N8231-100-2, orange-yellow slightly gummy solid, 7.7 g LCMS (Method B): Rt=1.17 min, MH+ 380
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110 - 130℃; for 1.5h;microwave irradiation; Sealed tube;
Intermediate 15: 1 ,1-Dimethylethyl (3 ~)-3-fr(7-chloropyridor3,4-blpyrazin-5- yl)amino1methyl)-3-fluoro-1 -piperidinecarboxylate; To a solution of 1 , 1-dimethylethyl (3f~)-3-(aminomethyl)-3-fluoro-1- piperidinecarboxylate (2.32g, l O.OOmmol) in N-methyl-2-pyrrolidone (NMP) (5ml) was added <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (2g, lO.OOmmol) and diisopropylethylamine (3.49ml, 20.00mmol). This was heated at 130C in a Biotage Microwave for 1 h. The reaction had not gone to completion and so further amine (380mg) was added and it was again heated to 1 10C for 30min in a microwave. The reaction was partitioned between ethyl acetate and aqueous ammonium chloride. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine and passed through a hydrophobic frit, and concentrated in vacuo to yield a crude brown oil. This was dissolved in DCM and purified through silica (50g) eluting with an ethyl acetate/DCM gradient. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a yellow-orange gummy solid (3.13g)LCMS (Method B): Rt
3.13 g
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110 - 130℃; for 1.5h;Microwave irradiation;
Intermediate 15: 1,1-Dimethylethyl (3R)-3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate To a solution of 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (2.32 g, 10.00 mmol) in N-methyl-2-pyrrolidone (NMP) (5 ml) was added <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (2 g, 10.00 mmol) and diisopropylethylamine (3.49 ml, 20.00 mmol). This was heated at 130 C. in a Biotage Microwave for 1 h. The reaction had not gone to completion and so further amine (380 mg) was added and it was again heated to 110 C. for 30 min in a microwave. The reaction was partitioned between ethyl acetate and aqueous ammonium chloride. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine and passed through a hydrophobic frit, and concentrated in vacuo to yield a crude brown oil. This was dissolved in DCM and purified through silica (50 g) eluting with an ethyl acetate/DCM gradient. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a yellow-orange gummy solid (3.13 g) LCMS (Method B): Rt=1.24 min, MH+=395.8
Intermediate 29: 1 ,1-Dimethylethyl 3-{r(7-chloropyridor3,4-frlpyrazin-5- yl)oxy1methyl)-4,4-difluoro-1 -piperidinecarboxylate; 1 , 1-Dimethylethyl 4,4-difluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (207mg, 0.825mmol) was dissolved in dry Nu,Nu-dimethylformamide (DMF) (5ml) and sodium hydride (45.0mg, 1.125mmol) was added under nitrogen at room temperature. After ~ 60min, <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (150mg, 0.750mmol) was added and the reaction was stirred at room temperature under nitrogen for 2h. The reaction was quenched by the addition of sat. ammonium chloride solution and extracted with ethyl acetate. The aqueous layer was extracted further with ethyl acetate. The combined organics were washed with water, dried using a hydrophobic frit and evaporated in vacuo to give an orange oil (369mg). The residue was loaded in dichloromethane and purified on silica (50g) column using a 0-100% ethyl acetate/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as an orange oil (163mg).LCMS (Method B): Rt = 1.25min, MH+ = 415
163 mg
Intermediate 29: 1,1-Dimethylethyl 3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)oxy]methyl}-4,4-difluoro-1-piperidinecarboxylate 1,1-Dimethylethyl 4,4-difluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (207 mg, 0.825 mmol) was dissolved in dry N,N-dimethylformamide (DMF) (5 ml) and sodium hydride (45.0 mg, 1.125 mmol) was added under nitrogen at room temperature. After 60 min, <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (150 mg, 0.750 mmol) was added and the reaction was stirred at room temperature under nitrogen for 2 h. The reaction was quenched by the addition of sat. ammonium chloride solution and extracted with ethyl acetate. The aqueous layer was extracted further with ethyl acetate. The combined organics were washed with water, dried using a hydrophobic frit and evaporated in vacuo to give an orange oil (369 mg). The residue was loaded in dichloromethane and purified on silica (50 g) column using a 0-100% ethyl acetate/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as an orange oil (163 mg). LCMS (Method B): Rt=1.25 min, MH+=415
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;microwave irradiation;
Intermediate 37: 1 ,1 -dimethylethyl 3-{r(7-chloropyridor3,4-fllpyrazin-5- yl)amino1methyl)-4,4-difluoro-1 -piperidinecarboxylate (Isomer 2); 5,7-Dichloropyrido[3,4-b]pyrazine (620mg, 3.10mmol) was dissolved in N-methyl-2- pyrrolidinone (NMP) (5mL) and to this was added DIPEA (0.601 ml_, 4.65mmol) and 1 , 1-dimethylethyl 3-(aminomethyl)-4,4-difluoro-1-piperidinecarboxylate (776mg, 3.10mmol). This was heated in a microwave at 130C for 30min. The reaction mixture was partitioned between ethyl acetate and water. The aqueous was re-extracted twice with ethyl acetate and the combined organic layers washed with brine, dried over a hydrophobic frit and concentrated in vacuo to yield a brown oil. It was dissolved in DCM and passed through silica (100g) eluting with a 10-50% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a yellow solid, 1.0g.Chiral separation was achieved (Sample preparation: Sample dissolved in ethanol (30ml) sonicating and heating with air gun as required. 4-5ml injections were then pumped onto a preparative scale Whelk-0 (S, S) column (2 inch). Details as follows: Column - Whelk-0 (S, S) (50x250mm, l Omicron); Detection - UV DAD - 300nm (bandwidth 180nm, reference 550nm (bandwidth 100nm)); Flow Rate - 70ml/min; Mobile Phase A: Heptane; Mobile Phase B: I PA; Isocratic method (premixed) 5% B; Runtime - 60min; Number of runs - 8) to yield the title compound (second eluting peak from the chiral column) as a yellow solid (441 mg).LCMS (Method B): Rt =1.27min, MH+ =414 The following intermediate was obtained as the first eluting peak from the chiral separation above:; Intermediate 38: 1 ,1 -dimethylethyl 3-{r(7-chloropyridor3,4-fllpyrazin-5- yl)amino1methyl)-4,4-difluoro-1 -pipendinecarboxylate (Isomer 1); LCMS (Method B): Rt =1.27min, MH+ =414The following intermediate was prepared similarly:Intermediate 39: 1 ,1 -dimethylethyl 5-{r(7-chloropyridor3,4-fllpyrazin-5-LCMS (Method B): Rt =1.24min, MH+= 414
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;Microwave irradiation;
Intermediate 37: 1,1-dimethylethyl 3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-4,4-difluoro-1-piperidinecarboxylate (Isomer 2) 5,7-Dichloropyrido[3,4-b]pyrazine (620 mg, 3.10 mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (5 mL) and to this was added DIPEA (0.601 mL, 4.65 mmol) and 1,1-dimethylethyl 3-(aminomethyl)-4,4-difluoro-1-piperidinecarboxylate (776 mg, 3.10 mmol). This was heated in a microwave at 130 C. for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The aqueous was re-extracted twice with ethyl acetate and the combined organic layers washed with brine, dried over a hydrophobic frit and concentrated in vacuo to yield a brown oil. It was dissolved in DCM and passed through silica (100 g) eluting with a 10-50% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a yellow solid, 1.0 g. Chiral separation was achieved (Sample preparation: Sample dissolved in ethanol (30 ml) sonicating and heating with air gun as required. 4-5 ml injections were then pumped onto a preparative scale Whelk-O(S,S) column (2 inch). Details as follows: Column-Whelk-O(S,S) (50×250 mm, 10 micron); Detection-UV DAD-300 nm (bandwidth 180 nm, reference 550 nm (bandwidth 100 nm)); Flow Rate-70 ml/min; Mobile Phase A: Heptane; Mobile Phase B: IPA; Isocratic method (premixed) 5% B; Runtime-60 min; Number of runs-8) to yield the title compound (second eluting peak from the chiral column) as a yellow solid (441 mg). LCMS (Method B): Rt=1.27 min, MH+=414 The following intermediate was obtained as the first eluting peak from the chiral separation above: Intermediate 38: 1,1-dimethylethyl 3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-4,4-difluoro-1-piperidinecarboxylate (Isomer 1) LCMS (Method B): Rt=1.27 min, MH+=414
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;microwave irradiation;
Intermediate 25: 1 ,1-Dimethylethyl (3 ~)-3-fr(7-chloropyridor3,4-blpyrazin-5- yl)amino1methylV4-methyl-1-piperazinecarboxylate; 1 , 1-Dimethylethyl (3S)-3-(aminocarbonyl)-4-methyl-1-piperazinecarboxylate (0.5g, 2.055mmol) was dissolved in dry tetrahydrofuran (THF) (10ml) and borane- tetrahydrofuran complex (8ml, 8.00mmol) was added. The reaction was refluxed under nitrogen overnight. A further portion of borane-tetrahydrofuran complex (8ml, 8.00mmol) was added and the reaction was refluxed under nitrogen for a further 24h. After cooling, the reaction was cooled further in an ice bath and quenched by the addition of methanol (25ml) and 1 M HCI (5ml), stirred for 90min and left standing at room temperature for 2h. Ethyl acetate (25ml) was added and the layers were separated. The aqueous was extracted with ethyl acetate. The combined organics were dried using a hydrophobic frit and evaporated in vacuo to give a white solid (270mg). TLC (10% MeOH/DCM, KMn04) looked like starting material. The aqueous layer was neutralised with 2M NaOH and extracted with DCM (x3). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated in vacuo to give 1 , 1-dimethylethyl (3f~)-3-(aminomethyl)-4-methyl-1- piperazinecarboxylate as a crude colourless oil (313mg). 1 , 1-dimethylethyl (3R)-3- (aminomethyl)-4-methyl-1-piperazinecarboxylate (143mg, 0.624mmol) and diisopropylethylamine (0.131 ml, 0.750mmol) were added to a solution of 5,7- dichloropyrido[3,4-b]pyrazine (100mg, 0.500mmol) in dry N-methyl-2-pyrrolidone (NMP) (2ml). The reaction was heated at 130C in the microwave for 30min. After cooling, the reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (x2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give an orange oil. The residue was loaded in dichloromethane and purified on silica (25g) using a 0-100% ethyl acetate/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as yellow oil (162mg).LCMS (Method A): Rt = 1.2min, MH+ = 393/395
162 mg
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.5h;Microwave irradiation;
1,1-dimethylethyl (3R)-3-(aminomethyl)-4-methyl-1-piperazinecarboxylate (143 mg, 0.624 mmol) and diisopropylethylamine (0.131 ml, 0.750 mmol) were added to a solution of <strong>[1379338-74-5]5,7-dichloropyrido[3,4-b]pyrazine</strong> (100 mg, 0.500 mmol) in dry N-methyl-2-pyrrolidone (NMP) (2 ml). The reaction was heated at 130 C. in the microwave for 30 min. After cooling, the reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (*2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give an orange oil. The residue was loaded in dichloromethane and purified on silica (25 g) using a 0-100% ethyl acetate/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as yellow oil (162 mg). LCMS (Method A): Rt=1.2 min, MH+=393/395
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 4h;
A) (S)-terf-butyl 3-((7-chloropyrido[4,3-ib]pyrazi n-5-ylami no)methyl)piperidi ne- 1 -carboxylate.A solution of (S)-teri-butyl 3-(aminomethyl)piperidine-1 -carboxylate (100 mg, 0.5 mmol), 5,7-dichloropyrido[4,3-£>]pyrazine (100 mg, 0.5 mmol) and DIPEA (77 mg, 0.6 mmol) in THF (5 mL) was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was treated with ethyl acetate, with brine, and concentrated to give the crude title compound.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 4h;
(A) (S)-terf-butyl 3-((7-chloropyrido[4,3-ib]pyrazi n-5-ylami no)methyl)piperidi ne- 1 -carboxylate.[0123] A solution of (S)-teri-butyl 3-(aminomethyl)piperidine-1 -carboxylate (100 mg, 0.5 mmol), 5,7-dichloropyrido[4,3-£>]pyrazine (100 mg, 0.5 mmol) and DIPEA (77 mg, 0.6 mmol) in THF (5 ml_) was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was treated with ethyl acetate, with brine, and concentrated to give the crude title compound.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 4h;
A solution of <strong>[140645-24-5](S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate</strong> (100 mg, 0.5 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (100 mg, 0.5 mmol) and DIPEA (77 mg, 0.6 mmol) in THF (5 mL) was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was treated with ethyl acetate, with brine, and concentrated to give the crude title compound.
(A) /V-(3-ami nopropyl)-7-chloropyrido[4,3-ib]pyrazi n-5-ami ne.A solution of propane-1 ,3-diamine (890 mg, 12 mmol) and 5,7-dichloropyrido[4,3- £>]pyrazine (600 mg, 3 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. The volatiles were evaporated, and the residue was purified by chromatography to afford the title compound. MS (m/z): 238 (M+H)+.
In methanol; at 20℃; for 4h;
(A) A-(3-ami nopropyi)-7-chSo ropyrido[4,3-&] pyrazi n-5-ami ne.[01 67] A solution of propane-1 ,3-diamine (890 mg, 12 mmol) and 5,7- dichloropyrido[4,3-£>]pyrazine (600 mg, 3 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. The volatiles were evaporated, and the residue was purified by chromatography to afford the title compound. MS (m/z): 238 (M+H)+.
(A) methyl 3-(7-chloropyrido[4,3-ib]pyrazi n-5-ylamino)propanoate.A solution of methyl 3-aminopropanoate hydrochloride (4.88 mmol), Et3N (6.50 mmol) and 5,7-dichloropyrido[4,3-£>]pyrazine (3.25 mmol) in THF (10 ml_) was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 267 (M+H)+.
With triethylamine; In tetrahydrofuran; at 20℃;
(A) methyl 3-(7-chloropyrido[4,3-ib]pyrazi n-5-ylamino)propanoate.[01 62] A solution of methyl 3-aminopropanoate hydrochloride (4.88 mmol), Et3N (6.50 mmol) and 5,7-dichloropyrido[4,3-£>]pyrazine (3.25 mmol) in THF (10 mL) was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 267 (M+H)+.
C) (9/-/-fluoren-9-yl)methyl 5-(7-chloropyrido[4,3-£>]pyrazi n-5- yl)hexahyd ropy rrolo[3,4-£>] pyrrole- 1 (2H)-carboxylateThe mixture of (9/-/-fluoren-9-yl)methyl hexahydropyrrolo[3,4-£>]pyrrole-1 (2/-/)- carboxylate (100 mg, 0.5 mmol) and 5,7-dichloropyrido[4,3-£>]pyrazine (600 mg, 1 .8 mmol) in dioxane was stirred at 0 C for 30 minutes and then at room temperature for 4 hours. The mixture was concentrated, and the residue was purified bychromatography to give the title compound. MS (m/z): 498 (M+H)+.
In 1,4-dioxane; at 0 - 20℃; for 4.5h;
The mixture of (9H-fluoren-9-yl)methyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (100 mg, 0.5 mmol) and <strong>[1379338-74-5]5,7-dichloropyrido[4,3-b]pyrazine</strong> (600 mg, 1.8 mmol) in dioxane was stirred at 0 C. for 30 minutes and then at room temperature for 4 hours. The mixture was concentrated, and the residue was purified by chromatography to give the title compound. MS (m/z): 498 (M+H)+.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Reflux;
(E) ie/t-buty. 3-((7-chioropyrido[4.3-£?]pyrazi n-5-ylami no)methyl)-4- hydroxypiperidi ne-1 -carboxylate.5,7-dichloropyrido[4,3-£>]pyrazine (3.6 g, 18 mmol) and DIPEA (2.8 g, 21 .6 mmol) was added to a solution of ferf-buty. terf-buty. 3-(aminomethyi)-4-{terf~butyldimethyisiiyioxy)piperidine-1 -carboxylate (6.2 g, 18 mmol) in THF (20 mL) and the mixture was refluxed overnight. The volatile components were evaporated and the residue was extracted with ethyl acetate. Ethyl acetate was washed with brine and dried. The solvent was removed and the residue was re-dissolved in THF (16 mL) and TBAF was added in. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with brine, then dried, filtered, and concentrated in vacuo. The crude residue was purified by flashchromatography to give the title compound (3.35 g, 47% yield). MS (m/z): 394(M+H)+.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Reflux;
<strong>[1379338-74-5]5,7-dichloropyrido[4,3-b]pyrazine</strong> (3.6 g, 18 mmol) and DIPEA (2.8 g, 21.6 mmol) was added to a solution of tert-butyl tert-butyl 3-(aminomethyl)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (6.2 g, 18 mmol) in THF (20 mL) and the mixture was refluxed overnight. The volatile components were evaporated and the residue was extracted with ethyl acetate. Ethyl acetate was washed with brine and dried. The solvent was removed and the residue was re-dissolved in THF (16 mL) and TBAF was added in. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with brine, then dried, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography to give the title compound (3.35 g, 47% yield). MS (m/z): 394 (M+H)+.
(9H-fluoren-9-yl)methyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate hydrochloric acid[ No CAS ]
[ 1415794-35-2 ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane; at 0 - 20℃; for 4.5h;
(C) (9/-/-fluoren-9-yl)methyl 5-(7-chloropyrido[4,3-£>]pyrazi n-5- yl)hexahyd ropy rrolo[3,4-£>] pyrrole- 1 (2H)-carboxylate[0129] The mixture of (9/-/-fluoren-9-yl)methyl hexahydropyrrolo[3,4-£>]pyrrole-1 (2/-/)- carboxylate (100 mg, 0.5 mmol) and 5,7-dichloropyrido[4,3-£>]pyrazine (600 mg, 1 .8 mmol) in dioxane was stirred at 0 C for 30 minutes and then at room temperature for 4 hours. The mixture was concentrated, and the residue was purified by chromatography to give the title compound. MS (m/z): 498 (M+H)+.
(S)-tert-butyl 3-(1-hydroxyethyl)pyrrolidine-1-carboxylate[ No CAS ]
(S)-1-(1-(7-chloropyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(D) (S)-1 -(1 -(7-chloropyrido[4,3-ib]pyrazi n-5-yl)pyrrolidi n-3-yl)ethanol .[01 60] (S)-teri-butyl 3-(1 -hydroxyethyl)pyrrolidine-1 -carboxylate was treated with HCI solution (in EtOAc, 5 mL) at room temperature for 2 hours . The volatiles were removed under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL). To the resulted THF solution, DIPEA (570 mg, 4.4 mmol) and 5,7- dichloropyrido[4,3-£>]pyrazine (400 mg, 2.0 mmol) were added, and the reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate, washed with brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 279 (M+H)+.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;
E) terf-butyl 3-(tert-butyldi methylsilyloxy)-5-((7-chloropyrido[4,3-ib]pyrazi n-5- ylami no)methyl)piperidi ne-1 -carboxylate.[01 13] A solution of terf-butyl 3-(aminomethyl)-5-(ieri-butyldimethylsilyloxy)piperidine- 1 -carboxylate (4.74 g, 13.7 mmol), 5,7-dichloropyrido[4,3-£>]pyrazine (2.75 g, 13.7 mmol) and DIPEA (2.12 g, 16.4 mmol) in THF (20 mL) was stirred at roomtemperature for 48 hours. The volatiles were removed under reduced pressure and the residue was treated with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;
A solution of tert-butyl 3-(aminomethyl)-5-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (4.74 g, 13.7 mmol), <strong>[1379338-74-5]5,7-dichloropyrido[4,3-b]pyrazine</strong> (2.75 g, 13.7 mmol) and DIPEA (2.12 g, 16.4 mmol) in THF (20 mL) was stirred at room temperature for 48 hours. The volatiles were removed under reduced pressure and the residue was treated with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
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