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Stage #1: 3-amino-N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide hydrochloride; dimethylaminoacetyl chloride hydrochloride In N,N-dimethyl-formamide at 5℃; Large scale;
Stage #2: With dipotassium hydrogenphosphate In ethanol; water; N,N-dimethyl-formamide at 10℃; for 2h; Large scale;
1
To 1 kg of 3-amino-N- {3 -[(2 -chloro-5 -methoxyphenyl)amino] quinoxalin-2- yl}benzenesulfonamide hydrochloride, add 8 volumes of dimethylformamide and 0.3 85 kgof 2-methylalanyl chloride hydrochloride at 5°C. After completion of the reaction, heat at50°C and add a solution made of K2HPO4 (1.4 kg), water (16.5 volumes) and ethanol (7.1 volumes). Cool down the reaction mixture at 10°C, stir 2 hours at 10°C anf filter. The cake is washed 3 times with 10 volumes of water and dried under vacuum.Crude N-(3 - { [(2Z)-3 - [(2-chloro-5 -methoxyphenyl)amino]quinoxalin-2 (1 1])-ylidene]sulfamoyl}phenyl)-2-methylalaninamide was recrystallized fromdimethylacetamide and toluene using charcoal, followed by reslurry in ethanol, and finally washings by isopropanollethanol mixture, resulting in the compound in pure form.Surprisingly and unexpectedly, the solid state compound recovered from this process was entirely N-(3 - { [(2Z)-3 - [(2-chloro-5 -methoxyphenyl)amino]quinoxalin-2 (1 1])-ylidene]sulfamoyl}phenyl)-2-methylalaninamide. That is, while a number of tautomeric forms of the compound may exist, the instant process yielded a solid compound of only N- (3- { [(2Z)-3 - [(2-chloro-5 -methoxyphenyl)amino] quinoxalin-2( 1 1])-ylidene] sulfamoyl} phenyl)-2-methylalaninamide and not a mixture of tautomers, as confirmed by ssNMR.
1
[00172] To 1 kg of 3-amino-N- {3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2- yl}benzenesulfonamide hydrochloride, add 8 volumes of dimethylformamide and 0.385 kg of 2-methylalanyl chloride hydrochloride at 5°C. After completion of the reaction, heat at 50°C and add a solution made of K2HP04 (1.4 kg), water (16.5 volumes) and ethanol (7.1 volumes). Cool down the reaction mixture at 10°C, stir 2 hours at 10°C anf filter. The cake is washed 3 times with 10 volumes of water and dried under vacuum. Resulting from this process is crude N-(3-{ [(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(lH)- ylidene]sulfamoyl}phenyl)-2-methylalaninamide in the form of pseudo-polymorph B. [00173] Crude N-(3 - { [(2Z)-3 -[(2-chloro-5 -methoxyphenyl)amino] quinoxalin-2( lH)- ylidene]sulfamoyl}phenyl)-2-methylalaninamide was recrystallized from dimethylacetamide and toluene using charcoal, followed by reslurry in ethanol, and finally washings by isopropanol/ethanol mixture, resulting in the compound in pure form. [00174] Surprisingly and unexpectedly, the solid state compound recovered from this process was entirely N-(3-{ [(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(lH)- ylidene]sulfamoyl}phenyl)-2-methylalaninamide. That is, while a number of tautomeric forms of the compound may exist, the instant process yielded a solid compound of only N- (3 - { [(2Z)-3 -[(2 -chloro -5 -methoxyphenyl)amino] quinoxalin-2( 1 H)- ylidene]sulfamoyl}phenyl)-2-methylalaninamide and not a mixture of tautomers, as confirmed by ssNMR.
Multi-step reaction with 3 steps
1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / Reflux; Large scale
2.1: platinum sulfide on carbon / tetrahydrofuran; water; ethanol / Reflux; Large scale
2.2: Reflux; Large scale
2.3: 20 °C / Large scale
3.1: N,N-dimethyl-formamide / 5 °C / Large scale
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