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Structure of 866777-98-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 866777-98-2 |
Formula : | C5H11NO3S |
M.W : | 165.21 |
SMILES Code : | CS(=O)(N(C)C[C@@H]1OC1)=O |
MDL No. : | MFCD30803369 |
InChI Key : | DUCXLFIAGRGXAB-YFKPBYRVSA-N |
Pubchem ID : | 60136062 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P361-P351-P334-P312 |
Class: | 8 |
UN#: | 1760 |
Packing Group: | Ⅲ |
* 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 |
---|---|---|
A 12 L flask was charged with water (1 L) followed by the addition NaOH (50% in water, 146.81 g, 1.835 mol). The beaker containing NaOH was washed with water (2×500 mL) and the washings were added to the flask. The mixture was stirred at room temperature for 10 min and cooled to 8 C. (N-methyl)methanesulfonamide (200.2 g, 1.835 mol) in water (500 mL) was added over 5 min. The mixture was stirred for 1 h at 4 C. and (S)-2-chloromethyloxirane (339.6 g, 3.67 mol) was added. The mixture was stirred for 20 h at 3-4 C. Dichloromethane (2 L) was added and the mixture was stirred for 30 min at 5-10 C. The two layers were allowed to separate over 10 min and collected. The organic layer (2.5 L) was added back to the 12 L flask and washed with 1 M H3PO4 (800 mL) and brine (800 mL). Dichloromethane was removed by rotary evaporation. To the crude product, toluene (400 mL) was added and removed by rotary evaporation. After three additional cycles of the toluene process, the title intermediate was obtained (228.2 g) which was used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
d. Synthesis of 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-aza-bicyclo[3.2.1]oct-3-yl}amide In a 3 L flask, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-azabicyclo[3.2.1]oct-3-yl}amide trifluoroacetate (105.0 g, 0.232 mol) was suspended in absolute ethanol (400 mL). To this suspension, NaOH (50% in water, 0.243 mol. 1.05 eq) dissolved in absolute ethanol (100 mL) was added at room temperature. The beaker containing the NaOH was washed with ethanol (2*50 mL) and the washings were added to the reaction mixture. After 30 min of stirring, a solution of <strong>[866777-98-2]N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide</strong> (62.0 g, 1.5 eq) in absolute ethanol (100 mL) was added. The mixture was refluxed for 2 h, cooled to room temperature and seed crystals of the title compound were added. After about 5 min of stirring a white solid formed. The mixture was cooled to 3-5 C. and stirred for 2 h. The white solid was filtered and the wet cake was washed with cold absolute ethanol (3*50 mL). The solid was dried under vacuum at 30 C. for 60 h to provide the title compound (93.8 g, water content by Karl Fischer method 2.03%). 1H NMR (CDCl3) δ ppm 10.52 (d, 1H), 8.83 (s, 1H), 7.75 (d, 2H), 7.64-7.60 (m, 2H), 7.28-7.26 m, 1H), 4.33-4.26 (m, 2H), 3.78-3.75 (m, 1H), 3.27-3.20 (m, 4H), 3.01 (s, 3H), 2.88 (s, 3H), 2.58-2.53 (m, 1H), 2.30-1.81(m, 11H), 1.68 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol;Heating / reflux; | <strong>[866777-98-2]N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide</strong> is dissolved in ethanol and benzyl amine (1-1.1 equiv) is added to the solution. (Alternatively, <strong>[866777-98-2]N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide</strong> is dissolved in ethanol and 1,1-diphenyl-methanamine (1-1.1 equiv) is added to the solution.) The mixture is refluxed until completion of the reaction. The product is isolated and extracted.The product of the previous step is deprotected by hydrogenation with H2 gas in methanol in the presence of acetic acid (0.9-1.1 equiv) using a palladium on carbon catalyst. After removal of the catalyst by filtration, the title intermediate is isolated and extracted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | <strong>[866777-98-2]N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide</strong> is dissolved in ethanol and benzyl amine (1-1.1 equiv) is added to the solution. (Alternatively, <strong>[866777-98-2]N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide</strong> is dissolved in ethanol and 1,1-diphenyl-methanamine (1-1.1 equiv) is added to the solution.) The mixture is refluxed until completion of the reaction. The product is isolated and extracted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; toluene; at 3 - 4℃; for 21h; | a. Preparation of N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide A 12 L flask was charged with water (1 L) followed by the addition sodium hydroxide (50% in water, 146.81 g, 1.835 mol). The beaker containing sodium hydroxide was washed with water (2*500 mL) and the washings were added to the flask. The mixture was stirred at room temperature for 10 min and cooled to ~8 C. (N-methyl)-methanesulfonamide (200.2 g, 1.835 mol) in water (500 mL) was added over 5 min. The mixture was stirred for 1 h at ~4 C. and (S)-2-chloromethyloxirane (339.6 g, 3.67 mol) was added. The mixture was stirred for 20 h at 3-4 C. Dichloromethane (2 L) was added and the mixture was stirred for 30 min at 5-10 C. The two layers were allowed to separate over 10 min and collected. The organic layer (~2.5 L) was added back to the 12 L flask and washed with 1 M phosphoric acid (800 mL) and brine (800 mL). Dichloromethane was removed by rotary evaporation. Toluene (400 mL) was added to the crude product, then removed by rotary evaporation. After three additional cycles of the toluene process, the title intermediate was obtained (228.2 g). | |
c. Preparation of N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide; A 12 L flask was charged with water (1 L) followed by the addition NaOH (50% in water, 146.81 g, 1.835 mol). The beaker containing NaOH was washed with water (2×500 mL) and the washings were added to the flask. The mixture was stirred at room temperature for 10 min and cooled to ˜8 C. (N-methyl)methanesulfonamide (200.2 g, 1.835 mol) in water (500 mL) was added over 5 min. The mixture was stirred for 1 h at ˜4 C. and (S)-2-chloromethyloxirane (339.6 g, 3.67 mol) was added. The mixture was stirred for 20 h at 3-4 C. Dichloromethane (2 L) was added and the mixture was stirred for 30 min at 5-10 C. The two layers were allowed to separate over 10 min and collected. The organic layer (˜2.5 L) was added back to the 12 L flask and washed with 1 M H3PO4 (800 mL) and brine (800 mL). Dichloromethane was removed by rotary evaporation. To the crude product, toluene (400 mL) was added and removed by rotary evaporation. After three additional cycles of the toluene process, the title intermediate was obtained (228.2 g) which was used without further purification in the next step. | ||
A 12 L flask was charged with water (1 L) followed by the addition NaOH (50% in water, 146.81 g, 1.835 mol). The beaker containing NaOH was washed with water (2×500 mL) and the washings were added to the flask. The mixture was stirred at room temperature for 10 min and cooled to 8 C. (N-methyl)methanesulfonamide (200.2 g, 1.835 mol) in water (500 mL) was added over 5 min. The mixture was stirred for 1 h at 4 C. and (S)-2-chloromethyloxirane (339.6 g, 3.67 mol) was added. The mixture was stirred for 20 h at 3-4 C. Dichloromethane (2 L) was added and the mixture was stirred for 30 min at 5-10 C. The two layers were allowed to separate over 10 min and collected. The organic layer (2.5 L) was added back to the 12 L flask and washed with 1 M H3PO4 (800 mL) and brine (800 mL). Dichloromethane was removed by rotary evaporation. To the crude product, toluene (400 mL) was added and removed by rotary evaporation. After three additional cycles of the toluene process, the title intermediate was obtained (228.2 g) which was used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
d. Synthesis of 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-aza-bicyclo[3.2.1]oct-3-yl}amide In a 3 L flask, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-azabicyclo[3.2.1]oct-3-yl}amide trifluoroacetate (105.0 g, 0.232 mol) was suspended in absolute ethanol (400 mL). To this suspension, NaOH (50% in water, 0.243 mol. 1.05 eq) dissolved in absolute ethanol (100 mL) was added at room temperature. The beaker containing the NaOH was washed with ethanol (2*50 mL) and the washings were added to the reaction mixture. After 30 min of stirring, a solution of <strong>[866777-98-2]N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide</strong> (62.0 g, 1.5 eq) in absolute ethanol (100 mL) was added. The mixture was refluxed for 2 h, cooled to room temperature and seed crystals of the title compound were added. After about 5 min of stirring a white solid formed. The mixture was cooled to 3-5 C. and stirred for 2 h. The white solid was filtered and the wet cake was washed with cold absolute ethanol (3*50 mL). The solid was dried under vacuum at 30 C. for 60 h to provide the title compound (93.8 g, water content by Karl Fischer method 2.03%). 1H NMR (CDCl3) δ ppm 10.52 (d, 1H), 8.83 (s, 1H), 7.75 (d, 2H), 7.64-7.60 (m, 2H), 7.28-7.26 m, 1H), 4.33-4.26 (m, 2H), 3.78-3.75 (m, 1H), 3.27-3.20 (m, 4H), 3.01 (s, 3H), 2.88 (s, 3H), 2.58-2.53 (m, 1H), 2.30-1.81 (m, 11H), 1.68 (d, 6H). | ||
In a 3 L flask, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-azabicyclo[3.2.1]oct-3-yl}amide trifluoroacetate (105.0 g, 0.232 mol) was suspended in absolute ethanol (400 mL). To this suspension, NaOH (50% in water, 0.243 mol. 1.05 eq) dissolved in absolute ethanol (100 mL) was added at room temperature. The beaker containing the NaOH was washed with ethanol (2×50 mL) and the washings were added to the reaction mixture. After 30 min of stirring, a solution of <strong>[866777-98-2]N-methyl-N-[(S)-2-oxiran-2-ylmethyl]methanesulfonamide</strong> (62.0 g, 1.5 eq) in absolute ethanol (100 mL) was added. The mixture was refluxed for 2 h, cooled to room temperature and seed crystals of the title compound were added. After about 5 min of stirring a white solid formed. The mixture was cooled to 3-5 C. and stirred for 2 h. The white solid was filtered and the wet cake was washed with cold absolute ethanol (3×50 mL). The solid was dried under vacuum at 30 C. for 60 h to provide the title compound (93.8 g, water content by Karl Fischer method 2.03%). 1H NMR (CDCl3) δ ppm 10.52 (d, 1H), 8.83 (s, 1H), 7.75 (d, 2H), 7.64-7.60 (m, 2H), 7.28-7.26 m, 1H), 4.33-4.26 (m, 2H), 3.78-3.75 (m, 1H), 3.27-3.20 (m, 4H), 3.01 (s, 3H), 2.88 (s, 3H), 2.58-2.53 (m, 1H), 2.30-1.81 (m, 1H), 1.68 (d, 6H).The seed crystals were obtained from a previous preparation of the title compound by the method of this example at smaller scale, in which crystallization occurred spontaneously. |
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