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Stage #1: 4-[4-(ethylsulfonyl)-1-piperazin-1-yl]phenylamine; C8H9ClN4O In 1-methyl-pyrrolidin-2-one at 80 - 90℃;
Stage #2: With hydrogenchloride In ethanol; water; dimethyl sulfoxide at 75℃; for 12h;
2.2.2.3; 3 Step 2.3
Cerdulatinib was synthesized by addition of Compound B to the NMP solution containing Compound A-i obtained from Step 2.2 after water wash and solvent swap. In different batches, addition of Compound B was conducted under three different conditions: basic conditions, acidic conditions and neutral conditions.“Basic conditions” Under the basic conditions, 1.0 equivalent of DIPEA was added at the beginning of the reaction at temperatures between 105-110 °C, and a reaction time was 12-16 hrs. After isolation, which comprises precipitating cerdulatinib with water, filtration and washing, cerdulatinib was obtained in 69 % yield with a purity of about 90 %.“Acid conditions” Under the acid conditions, 1.2 equivalents of aqueous HCl was addition at the beginning of the reaction. The reaction proceeded at a temperature of about 80 °C for 6-7 hrs to provide cerdulatinib HCl salt. At the end of reaction, i .2 equivalents of DIPEA were added, and after isolation, cerdulatinib was obtained with a purity of 93.4 % and a yield of 78 %.“Neutral conditions” Under the neutral conditions, no acids or bases were added at the beginning of the reaction. The reaction proceeded at 80-90 °C during 8-i6 hrs. At the end of the reaction, 1.0 equivalent of DIPEA was added in order to neutralize the HC1 generated during the reaction. Cerdulatinib was isolated in a 90 % yield with a purity of 9 1-92 %. Alternatively, the reaction was run at 90 °C for 8-12 hrs followed by addition of 1.0 equivalent of TEA. Water was then added and the resulting cerdulatinib precipitation was filtered and washed a mixture of NIVIP and water, followed by water wash, providing cerdulatinib with purities between 94.7 % and 97.9 % in average yield of 87 %.Example 3. Preparation of Cerdulatinib HC1 Salt. Cerdulatinib was dissolved in DMSO at 75 °C followed by addition of ethanol and 2equivalents of HC1 (iN). The mixture was stirred at 75 ± 5 °C for 12 hrs and then cooled to 20± 5 °C. The resulting suspension was filtrated and the solid was washed by slurrying in ethanolthree times in the reactor, before being dried. Cerdulatinib HC1 salt was obtained with a purityof 99.19% and yield of 92%.
Stage #1: C9H12N4OS With 3-chloro-benzenecarboperoxoic acid In 1-methyl-pyrrolidin-2-one at 0 - 25℃; for 1h; Large scale;
Stage #2: 4-[4-(ethylsulfonyl)-1-piperazin-1-yl]phenylamine at 40℃; for 21.3h; Large scale;
Stage #3: With hydrogenchloride In ethanol; water; dimethyl sulfoxide at 72.9 - 75℃; for 1h; Large scale;
1.2; 1.3; 4.4.3; 4.4.4 Step 2: Synthesis of Cerdulatinib
235 Kg of NMP, and 32.1 kg of Compound C PGE were charged to a reactor. The internal temperature was set at between 0-10 °C. 72.95 Kg of mCPBA were charged while keeping the temperature under 5 °C. The mixture was then warmed up to 25°C and stirred for 1 hr. IPC showed that residual content of Compound C was 0.00 % for oxidative reaction. The mixture was kept stirring at 25 °C for a further hour. To the above mixture, 40.05 kg of Compound B was added. The internal temperature was set at 40 °C and the mixture was stirred o.n. for 17 hrs and 17 minutes, and then for additional 4 hrs. IPC showed that residual content of Compound A-2 + Compound A-3 was 2.05 %. The mixture was cooled down to 3 °C, and a pre-cooled basic solution of water (642 L) and NaHCO3 (48 kg) was added to the mixture. The mixture was stirred for 1 hr and then water (193 L) was added keeping the internal temperature between 0-10 °C. The mixture was stirred for 40 minutes. Solid was isolated by filtration (filter-dryer equipped with 20 tm mesh) keeping squeezing the cake with both N2/vacuum for 51 hrs. Cerdulatinib PGU (106.9 kg) was then re-charged in the reactor and slurred at 25°C for9 hrs with water (1434 L). Solid was isolated by filtration (filter-dryer equipped with 20 tm mesh cloth) keeping squeezing the cake with both N2/vacuum for 60 hrs. Wet solid was respectively slurred and squeezing four times more in the filter-dryer using water (877 L). Solid was then forwarded to the filter-dryer for isolation and drying (43 °C undervacuum for 20 hrs). Cerdulatinib PGE overall yield was 88 % (63.76 kg) with purity of 90.84%. Step 3: Synthesis of Cerdulatinib HC1 Salt 252 Kg of DMSO and 56.2 kg of cerdulatinib were charged in the reactor. The mixture was warmed up to 75 °C and stirred till complete dissolution. 664 Kg of EtOH abs. was added and the reaction was stirred for 30 minutes. Keeping the internal temperature in between 70-80°C (72.9°C), an acidic solution made by mixing 347 kg of water and 43 kg of HC1 33% w/w was added. The reaction was stirred for further 30 minutes. The mixture was then cooled down to 20 °C and stirred for 19 hrs. Solid was then forwarded to the filter-dryer (20 tm mesh cloth) for isolation. Wet solid was respectively slurred and squeezing twice directly in the filter dryer using EtOH (1073 L), and then dried (at 35 °C under vacuum for 50 hrs). Cerdulatinib HC1 salt yield was 58.4 % (35.44 kg) with a purity of 99.41 %.
Multi-step reaction with 3 steps
1.1: triethylamine / dichloromethane / 2 h / 15 - 42 °C / Inert atmosphere
2.1: formamide; sodium ethanolate / N,N-dimethyl-formamide / 1 h / 0 - 50 °C / Large scale
3.1: 3-chloro-benzenecarboperoxoic acid / 1-methyl-pyrrolidin-2-one / 1 h / 0 - 25 °C / Large scale
3.2: 21.3 h / 40 °C / Large scale
3.3: 1 h / 72.9 - 75 °C / Large scale
4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: formamide; sodium ethanolate / N,N-dimethyl-formamide / 1 h / 0 - 50 °C / Large scale
2.1: 3-chloro-benzenecarboperoxoic acid / 1-methyl-pyrrolidin-2-one / 1 h / 0 - 25 °C / Large scale
2.2: 21.3 h / 40 °C / Large scale
2.3: 1 h / 72.9 - 75 °C / Large scale
Multi-step reaction with 3 steps
1.1: formamide; sodium ethanolate / N,N-dimethyl-formamide / 1 h / 0 - 50 °C / Large scale
2.1: 3-chloro-benzenecarboperoxoic acid / 1-methyl-pyrrolidin-2-one / 1 h / 0 - 25 °C / Large scale
2.2: 21.28 h / 40 °C / Large scale
3.1: hydrogenchloride / dimethyl sulfoxide; ethanol; water / 19.5 h / 20 - 80 °C / Large scale
3.2: 19.5 h / 20 - 80 °C / Large scale
Multi-step reaction with 2 steps
1.1: 3-chloro-benzenecarboperoxoic acid / 1-methyl-pyrrolidin-2-one / 1 h / 0 - 25 °C / Large scale
1.2: 21.28 h / 40 °C / Large scale
2.1: hydrogenchloride / dimethyl sulfoxide; ethanol; water / 19.5 h / 20 - 80 °C / Large scale
2.2: 19.5 h / 20 - 80 °C / Large scale
4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35.44 kg
252 Kg of DMSO and 56.2 kg of Compound I were charged in the reactor. The mixture was warmed up to 75 C and stirred till complete dissolution. 664 Kg of EtOH abs. was added and the reaction was stirred for 30 minutes. Keeping the internal temperature in between 70-80C (72.9C), an acidic solution made by mixing 347 kg of water and 43 kg of HC1 33% w/w was added. The reaction was stirred for further 30 minutes. The mixture was then cooled down to 20 C and stirred for 19 hours. Solid was then forwarded to the filter- dryer (20 pm mesh cloth) for isolation. Wet solid was respectively slurried and squeezing twice directly in the filter-dryer using EtOH (1073 L), and then dried (at 35 C under vacuum for 50 hours). Compound I hydrochloride salt yield was 58.4 % (35.44 kg) with a purity of 99.41 %.