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Structure of 74879-18-8 * Storage: {[proInfo.prStorage]}
* 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.
Stage #1: With L-Tartaric acid In water; acetic acid at 85℃; Stage #2: With calcium hydroxide In water at 80℃; for 5 h;
Thermometer, vacuum stirrer, four-necked flask 2L equipped with acooling tube, L- tartaric acid 270g (1.8 mol), acetic acid 108 g (1.8 mol), water 270g was added,was completely dissolved. Then, (±) -2- methylpiperazine 300g (3.0 mol), water 300g wasadded, and the reaction was heated 85 ° C or more, were completely dissolved. Then cooled to6874 ° C, (R) -2- methylpiperazine and L- diastereomers tartaric was added to precipitatecrystals, allowed to 1 hour aged at that temperature. Then, over a period of 5 hours and cooled to1218 ° C, and the precipitated crystals were filtered, diastereomeric salt 440g of wet biomass,liquid content 22.7wtpercent, optical purity of 92.3percent e. e. , R KaradaOsamuritsu Retrieving salt to theR-isomer of charge (±) in the 2-methyl piperazine, was 88percent. Then, charged 644g of water four-necked flask 2L, the resulting crystals 440g ((R) -2-methylpiperazine pure content = 132 g) were added. Furthermore, the addition of calciumhydroxide 162g (2.2mol), then heated to 80 ° C, and aged at that temperature for 5 hours.Cooled over a period of 2 hours up to 25 ° C, was filtered off precipitated crystals to remove thewet material crystal of 586g (mainly L- tartaric acid calcium). Get the filtrate 660 g, liberated with L- tartaric acid in the filtrate (R) -2- methylpiperazine were present 130 g. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, toluene 356g was added to the concentrate, a mixedsolution was heated under normal pressure and azeotroped with water and toluene in arms 84 to87 ° C, excluding the water. Then, toluene was distilled off 212g under reduced pressure. Theconcentrate was cooled to 47 ° C, (R) -2- methylpiperazine 0.01g was added as a seed crystal toprecipitate crystals, followed by aging for 1 hour at 47 ° C. Was cooled over 5 hours 05 ° C,and aged for 2 hours at 06 ° C. The precipitated crystals were taken out by filtration underreduced pressure, vacuum drying, the crystalline body (R) -2- methylpiperazine was 45gacquired. The resulting quality of (R) -2- methylpiperazine of the crystal body, chemical purity of100percent, an optical purity of 99.5percent e. e. In and, R KaradaOsamuritsu acquisition crystals for (R) -2-methylpiperazine in charge filtrate was 69percent. 1, illustrating the steps from Reference Example 1 to Example 1. Was the first crystallizationfrom ( "1 crystallization" was described as) (described as "crystallization") last crystallization upto six steps. Compared to the Comparative Example 2 step, short process, was able to get a goodoptically active 2-methylpiperazine of easy nature of handling. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, cyclopentyl methyl ether 356g added to theconcentrated solution, mixed solution was heated to normal pressure and azeotroped water andcyclopentyl methyl ether at 8487 ° C, except for the water. It was then distilled off cyclopentylmethyl ether 205g under reduced pressure. The concentrate was cooled to 47 ° C, (R) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals, followed by aging for1 hour at 47 ° C. Was cooled over 5 hours 05 ° C, and aged for 2 hours at 06 ° C. Theprecipitated crystals were taken out by filtration under reduced pressure, vacuum drying, thecrystalline body (R) -2- methylpiperazine was 44g acquired. The resulting quality of (R) -2-methylpiperazine of the crystal body, chemical purity of 100percent, an optical purity of 99.6percent e. e. Inand, R KaradaOsamuritsu acquisition crystals for (R) -2- methylpiperazine in charge filtrate was 68percent. Thermometer, vacuum stirrer, four-necked flask 1L equipped with a Dean-Starkapparatus, 33percent (S) -2- methylpiperazine solution 300.0g ((S) -2- methylpiperazine 100.0 g,Quality: Chemistry purity 99.9percent, optical purity of 80.0percent e.e. ) Were charged. Then stirred withtoluene 586.0g (5.86wt times / (S) -2- methylpiperazine). The solution was heated under normalpressure, arms 84 to 87 ° was azeotroped with water and toluene in C, except for water only.Then, toluene was distilled off 286g under reduced pressure. The concentrate was cooled to4350 ° C, (S) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals,followed by aging for 1 hour at 4350 ° C. Then it cooled over 2 hours to 0 to 5 ° C, and agedfor 2 hours at 05 ° C. The precipitated crystals were taken out by filtration under reducedpressure, vacuum drying, the crystalline body (S)-2-methylpiperazine 66.8g was obtained (67percentyield). The resulting quality of the crystal of (S) -2- methyl piperazine, the chemical purity of 100percent, an optical purity of 99.4percent e. e. A thermometer, a condenser, four-necked flask 1L equipped with astirrer, 33percent (S) -2- methylpiperazine solution 300.0g ((S) -2- methylpiperazine 100.0 g (1.0 mol),Quality : chemical purity 99.9percent, optical purity of 80.0percent e.e. ) Were charged to give concentrated,distilled to the (S) -2- methylpiperazine 13.3g (0.13 mol). (Yield: 13percent) obtained (S) -2- methylpiperazine was massive and solidified. Lumps of (S) -2- methylpiperazine by completely melted,to sample, it was subjected to assay of (S) -2- methylpiperazine. (S) -2- quality of methylpiperazine, chemical purity 99.9percent, optical purity of 80.0percent e. e. In purity does not change, thewater was contained approximately 10percent.
Reference：
[1] Patent: JP2016/37495, 2016, A, . Location in patent: Paragraph 0046-0052
Stage #1: With L-Tartaric acid In water; acetic acid at 85℃; Stage #2: With calcium hydroxide In water at 80℃; for 5 h;
Thermometer, vacuum stirrer, four-necked flask 2L equipped with acooling tube, L- tartaric acid 270g (1.8 mol), acetic acid 108 g (1.8 mol), water 270g was added,was completely dissolved. Then, (±) -2- methylpiperazine 300g (3.0 mol), water 300g wasadded, and the reaction was heated 85 ° C or more, were completely dissolved. Then cooled to6874 ° C, (R) -2- methylpiperazine and L- diastereomers tartaric was added to precipitatecrystals, allowed to 1 hour aged at that temperature. Then, over a period of 5 hours and cooled to1218 ° C, and the precipitated crystals were filtered, diastereomeric salt 440g of wet biomass,liquid content 22.7wtpercent, optical purity of 92.3percent e. e. , R KaradaOsamuritsu Retrieving salt to theR-isomer of charge (±) in the 2-methyl piperazine, was 88percent. Then, charged 644g of water four-necked flask 2L, the resulting crystals 440g ((R) -2-methylpiperazine pure content = 132 g) were added. Furthermore, the addition of calciumhydroxide 162g (2.2mol), then heated to 80 ° C, and aged at that temperature for 5 hours.Cooled over a period of 2 hours up to 25 ° C, was filtered off precipitated crystals to remove thewet material crystal of 586g (mainly L- tartaric acid calcium). Get the filtrate 660 g, liberated with L- tartaric acid in the filtrate (R) -2- methylpiperazine were present 130 g. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, toluene 356g was added to the concentrate, a mixedsolution was heated under normal pressure and azeotroped with water and toluene in arms 84 to87 ° C, excluding the water. Then, toluene was distilled off 212g under reduced pressure. Theconcentrate was cooled to 47 ° C, (R) -2- methylpiperazine 0.01g was added as a seed crystal toprecipitate crystals, followed by aging for 1 hour at 47 ° C. Was cooled over 5 hours 05 ° C,and aged for 2 hours at 06 ° C. The precipitated crystals were taken out by filtration underreduced pressure, vacuum drying, the crystalline body (R) -2- methylpiperazine was 45gacquired. The resulting quality of (R) -2- methylpiperazine of the crystal body, chemical purity of100percent, an optical purity of 99.5percent e. e. In and, R KaradaOsamuritsu acquisition crystals for (R) -2-methylpiperazine in charge filtrate was 69percent. 1, illustrating the steps from Reference Example 1 to Example 1. Was the first crystallizationfrom ( "1 crystallization" was described as) (described as "crystallization") last crystallization upto six steps. Compared to the Comparative Example 2 step, short process, was able to get a goodoptically active 2-methylpiperazine of easy nature of handling. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, cyclopentyl methyl ether 356g added to theconcentrated solution, mixed solution was heated to normal pressure and azeotroped water andcyclopentyl methyl ether at 8487 ° C, except for the water. It was then distilled off cyclopentylmethyl ether 205g under reduced pressure. The concentrate was cooled to 47 ° C, (R) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals, followed by aging for1 hour at 47 ° C. Was cooled over 5 hours 05 ° C, and aged for 2 hours at 06 ° C. Theprecipitated crystals were taken out by filtration under reduced pressure, vacuum drying, thecrystalline body (R) -2- methylpiperazine was 44g acquired. The resulting quality of (R) -2-methylpiperazine of the crystal body, chemical purity of 100percent, an optical purity of 99.6percent e. e. Inand, R KaradaOsamuritsu acquisition crystals for (R) -2- methylpiperazine in charge filtrate was 68percent. Thermometer, vacuum stirrer, four-necked flask 1L equipped with a Dean-Starkapparatus, 33percent (S) -2- methylpiperazine solution 300.0g ((S) -2- methylpiperazine 100.0 g,Quality: Chemistry purity 99.9percent, optical purity of 80.0percent e.e. ) Were charged. Then stirred withtoluene 586.0g (5.86wt times / (S) -2- methylpiperazine). The solution was heated under normalpressure, arms 84 to 87 ° was azeotroped with water and toluene in C, except for water only.Then, toluene was distilled off 286g under reduced pressure. The concentrate was cooled to4350 ° C, (S) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals,followed by aging for 1 hour at 4350 ° C. Then it cooled over 2 hours to 0 to 5 ° C, and agedfor 2 hours at 05 ° C. The precipitated crystals were taken out by filtration under reducedpressure, vacuum drying, the crystalline body (S)-2-methylpiperazine 66.8g was obtained (67percentyield). The resulting quality of the crystal of (S) -2- methyl piperazine, the chemical purity of 100percent, an optical purity of 99.4percent e. e. A thermometer, a condenser, four-necked flask 1L equipped with astirrer, 33percent (S) -2- methylpiperazine solution 300.0g ((S) -2- methylpiperazine 100.0 g (1.0 mol),Quality : chemical purity 99.9percent, optical purity of 80.0percent e.e. ) Were charged to give concentrated,distilled to the (S) -2- methylpiperazine 13.3g (0.13 mol). (Yield: 13percent) obtained (S) -2- methylpiperazine was massive and solidified. Lumps of (S) -2- methylpiperazine by completely melted,to sample, it was subjected to assay of (S) -2- methylpiperazine. (S) -2- quality of methylpiperazine, chemical purity 99.9percent, optical purity of 80.0percent e. e. In purity does not change, thewater was contained approximately 10percent.
Reference：
[1] Patent: JP2016/37495, 2016, A, . Location in patent: Paragraph 0046-0052
6
[ 5866-40-0 ]
[ 109-07-9 ]
[ 74879-18-8 ]
Yield
Reaction Conditions
Operation in experiment
86.1%
With acetic acid In water at 15 - 75℃; for 7 h;
Example 16 A 1-liter four-neck flask with a thermometer, stirrer and condenser was charged with 100.0 g of water and 90.0 g (= 0.600 mole) of D-tartaric acid, and after a homogeneous solution was formed, 200.4 g of an aqueous solution containing 50 wtpercent of racemic 2-methylpiperazine (pure 2-methylpiperazine content = 1.00 mole) and 36.0 g (= 0.600 mole) of acetic acid were added at room temperature. A homogeneous solution was formed at 70 to 75°C, and seed crystals were added at 65°C, being followed by aging for 1 hour. Then, cooling was carried out down to 15°C, taking 5 hours, being followed by aging at the temperature for 1hour. The obtained slurry was separated into a solid and a liquid, to obtain 172.1 g of a wet cake (pure 2-methylpiperazine content = 44.78 g = 0.447 mole) (optical purity = 92.6percent ee, S-isomer yield = 86.1percent based on the amount of supplied S-isomer). Then, a 1-liter four-neck flask with a thermometer, stirrer and condenser was charged with 130.0 g of water, and 154.9 g of the obtained cake (pure 2-methylpiperazine content = 40.30 g = 0.402 mole) was added at room temperature. The temperature was raised up to 75 to 85°C for dissolution, and seed crystals were added at 70°C, being followed by aging for 1 hour, cooling down to 15°C taking 5 hours and aging at the temperature for 1 hour. The obtained slurry was separated into a solid and a liquid, to obtain 107.0 g of a wet cake (pure 2-methylpiperazine content = 36.40 g = 0.363 mole) (optical purity = 99.5percent ee, S-isomer yield = 90.3percent based on the amount of supplied S-isomer). Then, a 1-liter four-neck flask with a thermometer, stirrer and condenser was charged with 300 g of water, and 100.0 g of the obtained wet cake (pure 2-methylpiperazine content = 34.01 g = 0.340 mole) was added. The temperature was raised up to 70°C for dissolution, and 34.42 g (0.442 mole, 1.3 molar times) of 95percent calcium hydroxide was added. Aging was carried out at 78 to 82°C for 3 hours, and solid-liquid separation was carried out to recover (S)-2-methylpiperazine. The 2-methylpiperazine content in the mother liquor was 33.38 g (= 0.333 mole) (recovery rate 98.0percent). From the obtained mother liquor, 230 g of water was distilled away, and 340 g of 1-butanol was added, concentration then being carried out at 60 to 70°C. In this case, Dean and Stark was installed to return the upper layer of the distillate into the distiller. When the water content in the distiller became 2.1 wtpercent, concentration was stopped, being followed by cooling down to 0°C. The 2-methylpiperazine content of the solution in the distiller was 32.38 g (= 0.323 mole) (recovery rate = 97.0percent). To the solution, 58.72 g (= 0.339 mole, 1.05 molar times) of benzyl chlorocarbonate was added dropwise while the dropwise added amount was adjusted to keep the temperature in the distiller at 0 to 10°C. Then, the temperature was raised to room temperature, being followed by aging for 2 hours, and concentration under reduced pressure was carried out at 60 to 70°C for distilling away 180 g (pure ZMP content = 68.50 g = 0.292 mole, reaction yield 90.5percent). Three hundred and eighty grams of toluene was added, and concentration under reduced pressure was carried out at 60 to 70°C, for distilling away 340 g. To the concentrate, 200 g of water was added, and 35percent hydrochloric acid water was used to adjust the pH to 1.2. Aging was carried out for 30 minutes, and the upper layer was removed. The same operation was repeated further twice, and 48percent sodium hydroxide aqueous solution was used to adjust the pH of the reaction solution to 12.0, being followed by addition of 140 g of toluene and stirring for 30 minutes. The lower layer was then removed, and 100 g of water was added, being followed by stirring. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70°C, toluene being then distilled away at 1.3 kPa and 80°C, to obtain 67.60 g of a concentrate. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 97.2 liquid chromatography area percent. The impurities showed 0.27 liquid chromatography area percent for benzyl alcohol, 0.02 liquid chromatography area percent for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.01 liquid chromatography area percent for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (2.44 liquid chromatography area percent for solvent toluene). Therefore, the total of impurities was 0.31 liquid chromatography area percent.
83.2%
With acetic acid In methanol; water at 25 - 72℃; for 14 h;
Example 15 A 2-liter four-neck flask with a thermometer, condenser and stirrer was charged with 200.4 g (= 2.00 moles) of racemic 2-methylpiperazine, 280.0 g of water and 96.0 g of methanol for perfect dissolution. Then, 300.4 g of 50 wtpercent D-tartaric acid aqueous solution (150.2 g = 1.000 mole of D-tartaric acid) was added at 40 to 45°C, and the temperature was further raised up to 72°C, being followed by addition of 120.2 g (= 2.00 moles) of acetic acid and aging at the temperature for 2 hours. The solvent composition was water/methanol = 81.8/18.2 (ratio by weight), and the amount of the solvent based on the racemic 2-methylpiperazine was 2.63 times by weight. Then, cooling was carried out down to 25°C, taking 12 hours, and precipitated crystals were collected by filtration. The obtained crystals were dried in vacuum, to obtain 214.8 g (= 0.858 mole) of a diastereomer salt. The optical purity of the salt was 93.9percent ee, and the yield of the S-isomer in the obtained salt based on the amount of the S-isomer in the supplied (+/-)-2-methylpiperazine was 83.2percent. Subsequently, a 1-liter flask was charged with 380 g of water, and the obtained 214.8 g of crystals {pure (S)-2-methylpiperazine content = 83.4 g} were added. Perfect dissolution was achieved at 80 to 85°C, and cooling was carried out down to 15°C, taking 12 hours. Precipitated crystals were collected by filtration and dried in vacuum to obtain 187.2 g of a salt. Its optical purity was 99.4percent ee, and the yield of the S-isomer in the obtained salt based on the amount of (S)-2-methylpiperazine in the supplied crystals was 89.8percent. A 500 ml four-neck flask with a thermometer, condenser and stirrer was charged with 150 g of water, and 185.0 g of (S)-2-methylpiperazine D-tartaric acid salt (= 0.739 mole, optical purity of 2-methylpiperazine = 99.4percent ee) obtained before and 69.1 g (= 0.863 mole) of 95percent pure calcium hydroxide were added. The slurry was heated up to 70 to 80°C, and stirred for 3 hours, then being cooled to room temperature. Subsequently, the non-dissolved salt was filtered away, to obtain the mother liquor. The mother liquor was GC-analyzed, and as a result, it was found that 68.7 g (= 0.686 mole) of optically active 2-methylpiperazine existed in the mother liquor (yield 92.8percent). Furthermore, as a result of HPLC analysis, the optical purity of (S)-2-methylpiperazine was 99.4percent ee. Then, water was distilled away till about 50 wtpercent was reached, being followed by addition of 1-butanol, and azeotropic dehydration was carried out till the water content of the system became less than 1 wtpercent. In a 1-liter four-neck flask, 50.0 g of the (S)-2-methylpiperazine (= 0.499 mole, optical purity 99.4percent ee) obtained before was placed, and 440 g of 1-butanol was added for dissolution. The solution was cooled down to 0°C, and 92.5 g (= 0.534 mole) of benzyl chlorocarbonate was added dropwise with the liquid temperature kept in a range from 0 to 8°C. Then, stirring was carried out at 0°C for 2 hours, and 300 g of 1-butanol was distilled away under reduced pressure, being followed by addition of 300 g of water. Subsequently 35percent hydrochloric acid water was used to adjust the pH to 1.0, and 220 g of toluene was added, being followed by stirring for 30 minutes. The upper layer was then removed, and the same amount of toluene was added again. The same operation was repeated to carry out washing operation. Subsequently 48percent sodium hydroxide aqueous solution was used to adjust the pH of the reaction solution to 12.1. In this case, white turbidity occurred due to liberated 1-benzyloxycarbonyl-3-methylpiperazine. To the white turbid solution, 400 g of toluene was added, and stirring water carried out for 30 minutes. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70°C in temperature. Subsequently toluene was distilled away to obtain 88.5 g of a concentrate. Eighty five point .zero grams of the obtained 1-benzyoxycarbonyl-3-methylpiperazine was fed to a thin film distiller (heating surface area 0.02 m2) using a liquid feed pump at 0.6 liter/h. The temperature of the heating medium was 150°C, and a low-boiling component was cut at a vacuum degree of 360 Pa, to obtain 82.8 g of a liquid remaining in the distiller. The liquid remaining in the distiller was again fed to the same thin film distiller at 0.6 liter/h using a liquid feed pump. The temperature of the heating medium was 220°C, and product distillation was carried out at 87 to 116 Pa in vacuum degree, to obtain 76.1 g of a distillate. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 99.4 liquid chromatography area percent. The impurities showed 0.25 liquid chromatography area percent for benzyl alcohol, 0.03 liquid chromatography area percent for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.02 liquid chromatography area percent for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (and 0.08 area percent for solvent toluene). Therefore, the total of impurities was 0.30 liquid chromatography area percent. Furthermore, the optical purity was 99.4percent ee.
Stage #1: With n-butyllithium In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: With chloro-trimethyl-silane In tetrahydrofuran for 1 h; Stage #3: at 20℃; for 1 h;
A solution of (S)-2-methylpiperazine (3.0 g, 30 mmol) in THF (300 mL) was added n- BuLi (2.4M, 25 mL, 60 mmol) dropwisely at room temperature. After the solution was stirred at room temperature for 30 min, TBSC1(4.5 g, 30 mmol) was added to the solution. The mixture was stirred for 1 hour and (Boc)20 (7.8 g, 36 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour and quenched with H20 (30 mL). The mixture was concentrated and then diluted with EA (300 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica weight: 20 g, eluted with EtOAc/MeOH 10: 1, Et3N 5percent) to give the title compound (1.15 g, 19percent) as oil.
To a solution of (S)-methylpiperazine (400 mg) in dichloromethane (20 mL) at 0° C. was added di-tert-butyl dicarbonate (871 mg). The reaction was stirred at room temperature for 4 h and then quenched with water (20 mL) and extracted into dichloromethane (2*40 mL). The combined organics were washed with saturated aqueous brine solution (40 mL), dried (MgSO4) and concentrated to give (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid (669 mg, 84percent).
84%
at 0 - 20℃; for 4 h;
To a solution of (S)-methylpiperazine (400 mg) in dichloromethane (20 mL) at0 °C was added di-tert-butyl dicarbonate (871 mg). The reaction was stirred at room <n="187"/>temperature for 4 h and then quenched with water (20 mL) and extracted into dichloromethane (2 x 40 mL). The combined organics were washed with saturated aqueous brine solution (40 mL), dried (MgSO4) and concentrated to give (S)-3-methyl-piperazine-l- carboxylic acid tert-butyl ester as a white solid (669 mg, 84percent).
80%
With triethylamine In dichloromethane for 5 h;
Step B tert-Butyl (3S)-3-methylpiperazine-1-carboxylate To a solution of (2S)-2-methylpiperazine (20.0 g, 0.200 mol) in methylene chloride (300 mL) and triethylamine (20.4 g, 0.202 mol) was added dropwise a solution of di-tert-butyl dicarbonate (44.0 g, 0.202 mol) in CH2Cl2 (100 mL) over 5 hrs. The mixture was washed with water, brine, and then dried over MgSO4 and concentrated. Column chromatography on silica (10-20percent MeOH in EtOAc) afforded 32.0 g (80percent) of the title compound as an oil. Step C tert-Butyl (3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazine-1-carboxylate
76.4%
With hydrogenchloride In methanol; water at 15 - 30℃; for 18 h;
Example 5 (0326) [0227] Compound 154 was prepared according to the reaction scheme in Figures 3 and 4. (0327) [0228] In a first step, compound 40 was prepared from compound 30 as follows: (0328) (0329) 30 40 (0330) [0229] Water (500 g, 5 w/wpercent) was charged to a reaction flask. Compound 30 (2- methylpiperazine) (100 g, 998.4 mmol, 1 eq.) was charged to the reaction flask with agitation. HC1 (36percent aqueous, 102.1 g, 1008 mmol, 1.01 eq.) and methanol (200 g) were charged to the reaction flask with agitation. A solution of Boc20 (222 g, 1008 mmol, 1.01 eq.) in methanol (200 g) was added dropwise to the reaction flask at 15 to 25 °C followed by stirring for 18 hours at 20 to 30°C. The flask contents were evaporated to dryness in vacuo at 40 to 50°C to form a residue. Water (500 g) was added to the residue and the mixture was stirred for 1 hours. The mixture was filtered and the collected solids were washed with water (50 g). The aqueous filtrate was extracted with ethylacetate (500 mL). The extracted aqueous phase was adjusted to a pH in excess of 12 with 30percent NaOH and was then extracted with ethylacetate (500 mL) three times. The organic phase was washed with brine (500 g) twice and was then dried with anhydrous Na2S04. The dried mixture was filtered and the collected solids were rinsed with ethylacetate (100 mL). The filtrate was concentrated to dryness in vacuo at 50 to 60°C and further concentrated under high vacuum (5 mm Hg) at 65 to 75°C for 3 hours to yield compound 40 (tert-butyl 3-methylpiperazine-l-carboxylate). The purity of compound 40 was 97.7 areapercent, the assay was 95.9percent and the yield was 76.4percent.
49%
at 0 - 20℃;
(S)-2-methylpiperazine (5.00 g, 49.9 mmol) was dissolved in DCM (150 mL). A solution of boc anhydride (5.47 g, 25.0 mmol) in DCM (50 mL) was added dropwise at 0° C. The reaction mixture was stirred at rt for 2 h. The solution was filtered and concentrated under reduced pressure. Water (100 mL) was added to the residue and it was filtered again. The filtrate was saturated with K2CO3 and extracted with Et2O (3.x.150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 4.92 g title compound (49percent) as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.03 (d, J=6.3 Hz, 3H) 1.45 (s, 9H) 1.53 (br. s, 1H) 2.38 (t, J=11.8 Hz, 1H) 2.65-2.72 (m, 1H) 2.74-2.76 (m, 2H) 2.92-2.95 (m, 1H) 3.92 (br. s, 2H).
562 mg
With triethylamine In dichloromethane at 0℃; for 2 h;
Description 146(S)-tert-butyl 3-methylpiperazine-1-carboxylate (1)146)NHBocTo a solution of (S)-2-methylpiperazine (500 mg) in DCM (5 mL) was added Et3N (1010 mg) and(Boc)20 (1198 mg) in DCM (3 mL) dropwise. The mixture was stirred at 0°C for 2 hours. DCM(10 mL), water (5 mL) and 30percent NaHSO4 (10 mL) aqueous solution were added to the reactionmixture. The resulted mixture was stirred for 10 mm, and to the aqueous layer was added saturatedNa2CO3 solution until pH = 8, extracted with isopropyl alcohol: chlorofonn1: 3 (5 x20 mL). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to afford the title compound (562 mg) as pale yellow oil, MS (ESI): C10H20N202 requires 200; found 201 [M+H].
Example 4 A 1-liter four-neck flask with a thermometer, condenser and stirrer was charged with 100.2 g (= 1. 00 mole) of 2-methylpiperazine provided as a racemic modification, 90.0 g (= 0.600 mole) of D-tartaric acid, 170 g of water and 36.0 g (= 0.600 mole) of acetic acid, being followed by heating up to 72°C and aging at the temperature for 2 hours. The amount of the solvent based on the amount of racemic 2-methylpiperazine was 1.69 times by weight. Then, cooling was carried out down to 15°C, taking 12 hours, and precipitated crystals were collected by filtration. The obtained crystals were dried in vacuum, to obtain 114.0 g (= 0.456 mole) of a diastereomer salt. The optical purity of the salt was 93.25percent ee, and the S-isomer yield in the obtained salt based on the amount of the S-isomer in the 2-methylpiperazine supplied as a racemic modification was 88.0percent. Then, a 500 ml flask was charged with 190 g of water, and 114.0 g of the obtained crystals {pure (S)-2-methylpiperazien content = 44.0 g} were added. Perfect dissolution was achieved at 80 to 85°C, being followed by cooling down to 15°C, taking 5 hours. Precipitated crystals were collected by filtration and dried in vacuum, to obtain 100.5 g of a salt. Its optical purity was 99.5percent ee, and the S-isomer yield in the obtained salt based on the amount of the (S)-2-methylpiperazine in the supplied crystals was 91.1percent. A 200 ml four-neck flask with a thermometer, condenser and stirrer was charged with 75 g of water, and 25.1 g of (S)-2-methylpiperazine D-tartaric acid salt (= 0.100 mole, optical purity of 2-methylpiperazine = 99.5percent ee) and 7.8 g (= 0.100 mole) of 95percent pure calcium hydroxide were added. The slurry was heated up to 70 to 80°C, and stirred for 3 hours, then being cooled to room temperature. Then, the non-dissolved solvent was filtered away to obtain the mother liquor. The mother liquor was GC-analyzed, and as a result, it was found that 9.2 g (= 0.0918 mole) of 2-methylpiperazine existed in the mother liquor (yield 91.8percent). Furthermore, from the result of HPLC analysis, the optical purity of (S)-2-methylpiperazine was 99.5percent ee. Subsequently concentration was carried out down to a water content of about 50 wtpercent, and 1-butanol was added. Then, azeotropic dehydration was carried out till the water content of the system became less than 1 wtpercent, and distillation under reduced pressure was carried out to isolate (S)-2-methylpiperazine. The optically active (S)-2-methylpiperazine (optical purity 99.5percent ee) obtained as described above was used to perform a reaction in quite the same way as the method of Example 1. Stirring was carried out for 2 hours at 0 to 5°C, being followed by stirring at room temperature for 12 hours. The reaction solution was analyzed, and as a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 84.6percent (based on the amount of 2-methylpiperazine), and its optical purity was 99.5percent ee, showing no decline of optical purity.
With triethylamine In N,N-dimethyl-formamide at 20℃; for 14 h;
Triethylamine (4.13 g, 3 niL, 40.8 mmol, 4 eq) is added to a solution of 6-chloro- nicotinonitrile (1.38 g, 10 mmol, leq), (S)-2-methyl- piperazine (1.0Og, 10 mmol, leq) in DMF (15 niL), and the resulting solution is stirred at rt for 14 h. A white precipitate of triethylamine hydrochloride forms in the course of the reaction. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The solid is further dried under high vacuum to yield the desired product as a white solid (1.4 g, 69percent). 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 8.38 (s, 1 H), 7.58 (d, J=9.60 Hz, 1 H), 6.59 (d, J=9.09 Hz, 1 H), 4.19 - 4.31 (m, 2 H), 3.08 - 3.15 (m, 1 H), 2.92 - 3.04 (m, 1 H), 2.81 - 2.91 (m, 2 H), 2.57 - 2.65 (m, 1 H), 1.15 (d. J=6.32 Hz, 3 H).
67%
With potassium carbonate In N,N-dimethyl acetamide at 60℃; for 2 h;
To a stirred solution of (2S)-2-methylpiperazine (0.30 g, 2.1 mmol) in DMA (6 mL), 6-chloropyridine-3-carbonitrile (0.29 g, 2.3 mmol) and K2C03 were added. The resultantreaction mixture was heated to 60 °C for 2 h (TLC indicated complete consumption ofstarting material). The reaction mixture was diluted with cold water (20 mL) and extractedwith EtOAc (3 x 25 mL). The combined organic extracts were washed with cold water (20mL) and brine (2 x 20 mL). The organic layer was separated, dried over Na2S04 andconcentrated under reduced pressure to give the crude residue which was purified by columnchromatography (100-200 silica gel, 10 g, 10percent MeOH-DCM) to furnish 6-[(3S)-3-methylpiperazin-1-yl]pyridine-3-carbonitrile (0.29 g, 67percent) as an off-white solid.LCMS: m/z: 203.4 [M+Ht.
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3954 - 3968
[2] Patent: WO2008/110611, 2008, A1, . Location in patent: Page/Page column 34
[3] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 110; 113
(S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine: To a solution of 2-bromonitrobenzene (0.600 g, 3.00 mmoi) in 1,4-dioxane (15 mL) was added <strong>[74879-18-8](S)-(+)-2-methylpiperazine</strong> (0.500 g, 0.500 mmol) and powdered K2C03 (15.0 mmol, 1.50 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was removed in vacuo. The resulting residue was purified by column chromatography (1/1 hexane/EtOAc followed by 4/1 EtOAc/MeOH), giving (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, 80%).
80%
With potassium carbonate; In 1,4-dioxane; methanol; hexane; ethyl acetate;
a) (S)-(+)-3-methyl-1-(2-nitrophenyl)piperazine. To a solution of 2-bromo-1-nitrobenzene (0.6 g, 3.0 mmol) in 1,4-dioxane (15 mL) was added <strong>[74879-18-8](S)-(+)-2-methylpiperazine</strong> (0.5 g, 0.5 mmol) and powdered K2CO3 (15.0 mmol, 1.5 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, 80%).
[1646] A solution of <strong>[74879-18-8](S)-(+)-2-methylpiperazine</strong> (0.50 g, 0.005 mol, CAS 74879-18-8, Aldrich 39,717-2, 99%) and 2-bromopyridine (5 mL, 0.05 mol) was heated to 120 C. for 14 hours. The reaction mixture was cooled to 23 C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice more with ethyl acetate. The aqueous phase was adjusted to pH 11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2×) and dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=12, 10 Hz, 1H), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=8, 6 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
67%
With sodium chloride; sodium hydrogencarbonate; sodium carbonate;
Example 25A (3S)-3-methyl-1-pyridin-2-ylpiperazine <strong>[74879-18-8](S)-(+)-2-Methylpiperazine</strong> (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120 C. for 14 hours. The reaction mixture was allowed to cool to 23 C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice with ethyl acetate. The aqueous phase was brought to pH ~11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2*) and dichloromethane (2*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
67%
With sodium chloride; sodium hydrogencarbonate; sodium carbonate;
Example 25A (3S)-3-methyl-1-pyridin-2-ylpiperazine <strong>[74879-18-8](S)-(+)-2-Methylpiperazine</strong> (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120 C. for 14 hours. The reaction mixture was allowed to cool to 23 C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice with ethyl acetate. The aqueous phase was brought to pH ~11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2*) and dichloromethane (2*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta 1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
67%
With sodium chloride; sodium hydrogencarbonate; sodium carbonate;
EXAMPLE 25A (3S)-3-methyl-1-pyridin-2-ylpiperazine <strong>[74879-18-8](S)-(+)-2-Methylpiperazine</strong> (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120 C. for 14 hours. The reaction mixture was allowed to cool to 23 C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice with ethyl acetate. The aqueous phase was brought to pH ~11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2*) and dichloromethane (2*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
67%
With sodium chloride; sodium hydrogencarbonate; sodium carbonate;
EXAMPLE 213A (3S)-3-methyl-1-(2-pyridinyl)piperazine A solution of <strong>[74879-18-8](S)-(+)-2-methylpiperazine</strong> (0.50 g, 0.005 mol, CAS 74879-18-8, Aldrich 39,717-2, 99%) and 2-bromopyridine (5 mL, 0.05 mol) was heated to 120 C. for 14 hours. The reaction mixture was cooled to 23 C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice more with ethyl acetate. The aqueous phase was adjusted to pH~11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2*) and dichloromethane (2*). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=12, 10 Hz, 1H), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=8, 6 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
67%
With sodium chloride; sodium hydrogencarbonate; sodium carbonate;
EXAMPLE 25A (3S)-3-methyl-1-pyridin-2-ylpiperazine <strong>[74879-18-8](S)-(+)-2-Methylpiperazine</strong> (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120 C. for 14 hours. The reaction mixture was allowed to cool to 23 C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice with ethyl acetate. The aqueous phase was brought to pH~11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2*) and dichloromethane (2*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta 1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
67%
With sodium chloride; sodium hydrogencarbonate; sodium carbonate;
Example 25A (3S)-3-methyl-1-pyridin-2-ylpiperazine <strong>[74879-18-8](S)-(+)-2-Methylpiperazine</strong> (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120 C. for 14 hours. The reaction mixture was allowed to cool to 23 C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice with ethyl acetate. The aqueous phase was brought to pH ~11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2*) and dichloromethane (2*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta 1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
4.3
A solution of the product of step 2 (2.1 g; 7.8 mmol), the N-BOC protected 2(S)-methyl piperazine (1.56g; 7.8 mmol - prepared from the reaction of commercial 2(S)-methyl piperazine with N-(tert-butoxy-carbonyloxy)phthalimide) and 2,2,6,6-tetramethyl piperidine (1.34 ml; 8 mmol) in 14 ml of dry CN3CN were heated at reflux until TLC indicated complete disappearance of the mesylate (16 h). The reaction mixture was cooled to RT, diluted with CH2Cl2 (50 ml) and washed with water (3 x 100 ml) and brine. The organic extract was dried over solid MgSO4 and then concentrated to obtain 2.8 g of a yellow gum. FSGC (20% EtOAc in hexanes) served to isolate the desired (S,S)-diastereomer (1.5g; 52%) and its benzylic epimer, the (R,S)-diastereomer (0.5g; 17%) for a combined 69% yield. TLC Rf = 0.75 (S,S) and 0.56 (R,S) in 25% EtOAc:hexanes.
To a solution of 2-(S)-methylpiperazine (3.79 g, 37.9 mmol) in CHCl3 (100 ML) was trityl chloride (10.56 g, 37.9 mmol) added in one portion.The exothermic reaction was stirred at ambient temperature for two hours, the organic phase was washed three times with water, dried (MgSO4) and the solvent was evaporated at reduced pressure to give 12.5 g (96%) of a colorless foam that solidified to a crisp over night. 1H NMR (CDCl3) delta1.06 (d, J=5.5 Hz, 3 H), 1.35 (m, 1 H), 1.61 (m, 1 H), 3.01 (m, 3 H), 3.14 (m, 1 H), 3.31 (m, 1 H), 7.08 (m, 3 H), 7.16 (m, 6 H), 7.35 (m, 6 H).13C NMR (CDCl3) delta18.17, 44.46, 46.68, 51.59, 54.03, 126.26, 127.13, 127.68, 129.07 br. The racemate of the title compound is reported in Bioorg. Med. Chem. Lett. 2000, 10, 2643-2646.
96%
In dichloromethane; at 20℃; for 2h;
To a solution of <strong>[74879-18-8](S)-2-methylpiperazine</strong> (1 g, 10 mmol, 1 eq) in DCM (30 mL) was added Trityl-CI (2.78 g, 10 mmol, 1 eq) portionwise at RT, then the reaction mixture was continued for 2 h. TLC analysis indicated formation of a less polar spot. The reaction mixture was quenched with water and extracted with EtOAc (3x50 mL). The combined organic layer was dried over Na2S04 then concentrated to give (S)-3-methyl-1-tritylpiperazine (3.3 g, 96%) as a colorless oil.
96%
In dichloromethane; at 20℃; for 2h;
To a solution of compound 1 (1 g, 10mmol, 1 eq) in DCM (30ml) was added Trityl-CI (2.78g, 10mmol, 1 eq) as portion wise at RT, then the reaction mixture was continued for 2h. TLC analysis indicated formation of a less polar spot. The reaction mixture was quenched with water and extracted with EtOAc (3x50ml_). The combined organic layer was dried over Na2S04 then concentrated to give compound 2 (3.3g, 96%) as a colorless oil.
With triethylamine; In dichloromethane; acetonitrile; at 5 - 20℃; for 1h;
(S)+-2-methylpiperazine (10 g) was dissolved in acetonitrile (140 ml) and cooled to 5-100C whereupon triethylamine (35 ml) was added, followed by drop wise addition of a solution of trityl chloride 27.9 (g) in DCM (80 ml). The reaction was stirred for 1 h at room temperature. The resulting slurry was cooled to approximately 00C then filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography (silica, 1-4% MeOH/ DCM as eluent) to give the sub-title compound (29 g).
In dichloromethane;
Step 1: (3S)-3-Methyl-1-Tritylpiperazine. To a solution of 2-(S)-methylpiperazine (2.62 g, 26.2 mmol) in dichloromethane (100 mL) was trityl chloride (7.30 g, 26.2 mmol) added and the mixture was stirred at ambient temperature for 1.5 h. The organic phase was washed (*1) with 1 M aqueous K2CO3, water, and brine. Drying (MgSO4) and solvent removal in vacuo furnished a quantitative yield of the title compound as a glassy oil which solidified upon standing. This material was used directly in the next step.
With triethylamine; In dichloromethane; acetonitrile; at 5 - 20℃; for 1h;
(S)+-2-methylpiperazine (10 g) was dissolved in acetonitrile (140 ml) and cooled to 5-10 C. whereupon triethylamine (35 ml) was added, followed by drop wise addition of a solution of trityl chloride (27.9 g) in DCM (80 ml). The reaction was stirred for 1 h at RT. The resulting slurry was cooled to approximately 0 C. then filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography (silica, 0-1% MeOH/DCM as eluent), then triturated with ether to give the sub-title compound as a white solid yield, 29.8 g.1H NMR CDCl3: delta 7.49-7.37 (6H, m), 7.26 (6H, t), 7.15 (3H, t), 3.38-3.28 (1H, m), 3.22 (1H, dd), 3.11-2.99 (3H, m), 1.74-1.6 (1H, m), 1.44-1.3 (1H, m), 1.11 (3H, d).
3-Methyl-1-[(3S)-3-methylpiperazinyl]-2-phenylpyrido[1,2-a]benzimidazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With triethylamine; In dimethyl sulfoxide; at 90℃; for 5h;
200 mg (0.63 mmol) of 1-chloro-3-methyl-2-phenylpyrido[1,2-a]benzimidazole-4-carbonitrile (I-8) was suspended in dimethylsulfoxide (4 ml), and 0.19 ml (1.32 mmol) of triethylamine and 82 mg (0.82 mmol) of (S) - (+) -2-methylpiperazine were added thereto, and heated with stirring at 90C for 5 hours. After restored to room temperature, water was added to the reaction mixture, and the resulting precipitate was collected by filtration and washed with n-hexane. The thus-obtained crude crystal was recrystallized from a mixed solvent of chloroform/ethyl acetate/n-hexane to obtain 141 mg (58 %) of the entitled compound as a yellow solid. MS(ESI)m/z:382(M+1)+.1H-NMR(DMSO-d6)delta: 0.76(3H, d, J=6.1Hz), 1.89(1H, t, J=10.5Hz), 2.17(3H, s) , 2.30(1H, dt, J=2.7, 11.2Hz), 2.70(1H, d, J=12.4Hz), 2.98-3.11(4H, m), 7.37-7.42(3H, m), 7.52-7.57(4H, m), 7.88(1H, d, J=8.0Hz), 8.80(1H, d, J=8.5Hz). IR(ATR): 2833, 2220, 1481, 1442 cm-1.
8-methyl-7-phenyl-6-[(3S)-methylpiperazin-1-yl]dipyrido[1,2-a;2',3'-d]imidazole-9-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With triethylamine; In DMF (N,N-dimethyl-formamide); at 80 - 90℃; for 12h;
To N,N-dimethylformamide (35 ml) solution of 350 mg (1.10 mmol) of 6-chloro-8-methyl-7-phenyldipyrido[1,2-a;2',3'-d]imidazole-9-carbonitrile (I-204) and 132 mg (1.32 mol) of (2S)-methylpiperazine was added 306 mul (2.20 mmol) of triethylamine, and the resulting mixture was stirred in an oil bath at 80 to 90C for 9.5 hours. Further, 132 mg (1.32 mmol) of (2S) -methylpiperazine was added thereto, and the mixture was stirred in an oil bath at 80 to 90C for 2.5 hours. After it was cooled and concentrated, the residue was dissolved in chloroform, and the organic layer was washed with aqueous saturated sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography. The solid obtained from the eluate with from chloroform/methanol (50/1 to 20/1, v/v) to chloroform/methanol/triethylamine (100/5/3, v/v/v) was stirred with methanol as slurry. This was filtered and dried under reduced pressure to obtain 255 mg (61 %) of the entitled compound as a yellow solid. HRMS(FAB)m/z:383.1989(Calcd for C23H23N6 383.1984).1H-NMR(CD3OD/CDCl3)delta: 0.88 and 0.96(3H, d each, J=6.0Hz), 2.11(1H, t, J=10.2Hz ), 2.24(3H, s), 2.50(1H, dt, J=3.0, 11.7Hz), 2.90-3.00(1H, m), 3.10-3.28(4H, m), 7.26-7.40(3H, m), 7.55-7.63(3H, m), 8.72(1H, dd, J=1.5, 4.8Hz), 8.98(1H, dd, J=1.5, 8.1Hz). IR(KBr): 2947, 2855, 2229, 1475, 1365, 775 cm-1.
A mixture of bromobenzene (300 mg), <strong>[74879-18-8](S)-2-methylpiperazine</strong> (230 mg), (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (48 mg), sodium tert-butoxide (266 mg), tris-(dibenzylideneacetone)dipalladium(0) (26 mg) and toluene (15 ml) was stirred at 100 C. for 4 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and saturated aqueous sodium hydrogencarbonate solution was added thereto. The organic layer was separated, washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol 20:1) to give the title compound in a pure form. [00204] 1H-NMR (300 MHz, CDCl3) delta 1.11 (d, J=6 Hz, 3H), 2.37 (dd, J=12 Hz,1 Hz, 1H), 2.72 (td, J=12 Hz,3 Hz, 1H), 2.95-3.18 (m, 3H), 3.52 (d, J=12 Hz, 2H), 6.82-6.98 (m, 3H), 7.22-7.29 (m,2H).
Example 43 : (S)-3-Methyl-piperazine-l-carboxylic acid ethyl ester; (S) -2-methyl-piperazine (500 mg, 4.99 mmol) was dissolved with stirring in dichloromethane (2.5 mL) and the solution was cooled to 0 C. Ethyl chloroformate (239 pL, 2.49 mmol) was added via a syringe drop wise. The mixture was allowed to warm to room temperature and stirred for 3h. When TLC analysis showed that the reaction was complete, the mixture was diluted with dichloromethane and washed with water. The organic phase was dried (Na2SO4), filtered and concentrated to yield the title compound, a yellowish liquid (315.8 mg, 73%). 1H NMR (300 MHz, CDC13) 8 = 0. 70 (d, J = 6.3 Hz, 3H); 0.91 (t, J = 7 Hz, 3H); 1.42 (s, broad, 1H) ; 2.06 (s, broad, 1H); 2.36 (m, 3H); 2.61 (m, 1H); 3.64 (s, broad, 2H); 3.78 (q, J = 7 Hz, 2H).
38%
In dichloromethane;
Example 32 Synthesis of 3 [(R)-METHYL-PIPERAZINE-1-CARBOXYLIC] acid ethyl ester and 3 (S)-Methyl- [PIPERAZINE-1-CARBOXYLIC] acid ethyl ester (R)-3-Methyl-piperazine-1-carboxylic acid ethyl ester (502 mg, 62%, a light brown oil) and [(S)-3-METHYL-PIPERAZINE-L-CARBOXYLIC] acid ethyl ester (307 mg, [38%,] a light brown oil) was obtained from (R) -2-Methyl-piperazine (1.0 g, 9.98 mmol) or (S)-2-Methyl- piperazine (1.0 g, 9.98 mmol) and [ETHYLCHLOROFORMATE] (0.45 ml, 4.71 mmol) in dichloromethane (5 mL). Purification was performed by silica gel chromatography. 1H- NMR (CDC13), [6] (ppm): 4.13 (q, 2 H), 3.91 (m, 2 H), 2.70 (m, 4 H), 2.42 (m, [1] H), 1.76 (br, s, 1 H), 1.23 (t, 3 H), 1.00 (d, 3 H).
In water; at 0 - 5℃; for 14.0h;Product distribution / selectivity;
Example 4 A 1-liter four-neck flask with a thermometer, condenser and stirrer was charged with 100.2 g (= 1. 00 mole) of 2-methylpiperazine provided as a racemic modification, 90.0 g (= 0.600 mole) of D-tartaric acid, 170 g of water and 36.0 g (= 0.600 mole) of acetic acid, being followed by heating up to 72C and aging at the temperature for 2 hours. The amount of the solvent based on the amount of racemic 2-methylpiperazine was 1.69 times by weight. Then, cooling was carried out down to 15C, taking 12 hours, and precipitated crystals were collected by filtration. The obtained crystals were dried in vacuum, to obtain 114.0 g (= 0.456 mole) of a diastereomer salt. The optical purity of the salt was 93.25%ee, and the S-isomer yield in the obtained salt based on the amount of the S-isomer in the 2-methylpiperazine supplied as a racemic modification was 88.0%. Then, a 500 ml flask was charged with 190 g of water, and 114.0 g of the obtained crystals {pure (S)-2-methylpiperazien content = 44.0 g} were added. Perfect dissolution was achieved at 80 to 85C, being followed by cooling down to 15C, taking 5 hours. Precipitated crystals were collected by filtration and dried in vacuum, to obtain 100.5 g of a salt. Its optical purity was 99.5%ee, and the S-isomer yield in the obtained salt based on the amount of the (S)-2-methylpiperazine in the supplied crystals was 91.1%. A 200 ml four-neck flask with a thermometer, condenser and stirrer was charged with 75 g of water, and 25.1 g of (S)-2-methylpiperazine D-tartaric acid salt (= 0.100 mole, optical purity of 2-methylpiperazine = 99.5%ee) and 7.8 g (= 0.100 mole) of 95% pure calcium hydroxide were added. The slurry was heated up to 70 to 80C, and stirred for 3 hours, then being cooled to room temperature. Then, the non-dissolved solvent was filtered away to obtain the mother liquor. The mother liquor was GC-analyzed, and as a result, it was found that 9.2 g (= 0.0918 mole) of 2-methylpiperazine existed in the mother liquor (yield 91.8%). Furthermore, from the result of HPLC analysis, the optical purity of (S)-2-methylpiperazine was 99.5%ee. Subsequently concentration was carried out down to a water content of about 50 wt%, and 1-butanol was added. Then, azeotropic dehydration was carried out till the water content of the system became less than 1 wt%, and distillation under reduced pressure was carried out to isolate (S)-2-methylpiperazine. The optically active (S)-2-methylpiperazine (optical purity 99.5%ee) obtained as described above was used to perform a reaction in quite the same way as the method of Example 1. Stirring was carried out for 2 hours at 0 to 5C, being followed by stirring at room temperature for 12 hours. The reaction solution was analyzed, and as a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 84.6% (based on the amount of 2-methylpiperazine), and its optical purity was 99.5%ee, showing no decline of optical purity.
With triethylamine; In dichloromethane; at 0 - 20℃; for 3.0h;
Benzyl chloroformate (16. 3ML) in DCM (30ml) was added dropwise to a cooled solution at 0C of (S)-2-METHYLPIPERAZINE (10G) in DCM (200ml) and triethylamine (14. 5MOL). The temperature was allowed to rise from 0C to rt and the reaction mixture was stirred at rt for 3h. The mixture was washed with saturated aqueous NAHCO3 (2x100ml). The DCM layer was dried (MGS04) and filtered. The filtrate was absorbed onto silica and then purified by column chromatography [silica gel, step gradient 0-10% MEOH (containing 10% 0.88 ammonia solution) in DCM] to give the title compound (D19) as an oil (10.18g). LCMS electrospray (+ve) 235 (MH+).
With triethylamine; In dichloromethane; at 20℃; for 3.0h;
Description 17 (3S)-1-Benzyloxycarbonyl-3-methylpiperazine (D17); (S)-2-methylpiperazine (10g) was dissolved in dry DCM (200ml). Triethylamine (14.5ml) was added and the reaction was cooled to 00C. Benzyl chloroformate (18.66g) in dry DCM (30ml) was added dropwise to the reaction mixture, which was then stirred at room temperature for 3h. The DCM layer was then washed with saturated bicarbonate and water, dried (MgSO4) and filtered and stripped to give an oil. The oil was absorbed onto silica and then purified by chromatography on a silica column (Flash, size E column) eluting with a gradient of MeOH/NH4OH in DCM (the MeOH/NH4OH component being comprised of methanol containing 10% 0.88 ammonia solution). The product was eluted with 6% of the NH4OH/MeOH component to give the title compound (D17) as an oil (10.18g). LCMS electrospray (+ve) 235 (MH+).
2-methylpiperazine-1,4-dicarboxylic acid dibenzyl ester[ No CAS ]
1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine[ No CAS ]
[ 84477-85-0 ]
[ 29906-54-5 ]
[ 100-51-6 ]
Yield
Reaction Conditions
Operation in experiment
Example 14 A 1-liter four-neck flask with a thermometer, condenser and stirrer was charged with 100.2 g (= 1.00 mole) of 2-methylpiperazine provided as a racemic modification, 90.0 g (= 0.600 mole) of D-tartaric acid, 170 g of water and 48.0 g (= 0.800 mole) of acetic acid, and the temperature was raised up to 72C, being followed by aging at the temperature for 2 hours. The amount of the solvent based on the amount of 2-methylpiperazine provided as a racemic modification was 1.70 times by weight. Then, cooling was carried out down to 15C, taking 12 hours, and precipitated crystals were collected by filtration. The obtained crystals were dried in vacuum, to obtain 112.4 g (= 0.449 mole) of a diastereomer salt. The optical purity of the salt was 94.4%ee, and the yield of the S-isomer in the obtained salt based on the amount of the S-isomer in the 2-methylpiperazine provided as a racemic modification was 87.3%. Then, a 500 ml flask was charged with 190 g of water, and 112.4 g of the obtained crystals {pure (S)-2-methylpiperazine content = 43.7 g} were added. Perfect dissolution was achieved at 80 to 85C, and cooling was carried out down to 15C, taking 12 hours. Precipitated crystals were collected by filtration and dried in vacuum to obtain 99.1 g of a salt. Its optical purity was 99.4%ee, and the yield of the S-isomer in the obtained salt based on the amount of (S)-2-methylpiperazine in the supplied crystals was 90.5%. A 1-liter four-neck flask with a thermometer, condenser and stirrer was charged with 300 g of water, and 98.3 g of the previously obtained salt of (S)-2-methylpiperazine and D-tartaric acid {pure (S)-2-methylpiperazine content = 39.2 g = 0.391 mole, optical purity of 2-methylpiperazine = 99.4%ee} and 39.6 g (= 0.508 mole) of 95% pure calcium hydroxide were added into the flask. The slurry was stirred in a range from 80 to 82C for 3 hours, and cooled to room temperature. Then, the non-dissolved salt (calcium tartarate) was filtered away, to obtain the mother liquor. The mother liquor was GC-analyzed, and as a result, it was found that 39.1 g (= 0.390 mole) of optically active 2-methylpiperazine existed in the mother liquor (yield 99.8%). Furthermore, as a result of HPLC analysis, the optical purity of (S)-2-methylpiperazine was 99.4%ee. Then, concentration was carried out to a water content of about 50 wt%, and 1-butanol was added, and azeotropic dehydration was carried out till the water content of the system became less than 1 wt%. In a 100 ml four-neck flask, 5.0 g of the obtained (S)-2-methylpiperazine (= 0.0499 mole, optical purity 99.4%ee) was placed, and 44 g of 1-butanol was added for dissolution. The solution was cooled down to 0C, and 9.25 g (= 0.0534 mole) of benzyl chlorocarbonate was added dropwise with the liquid temperature kept in a range from 0 to 8C. Then, stirring was carried out at 0C for 2 hours, and 30 g of 1-butanol was distilled away under reduced pressure. Subsequently 30 g of water was added, and 35% hydrochloric acid water was used to adjust the pH to 1.0. Then, 22 g of toluene was added, and stirring was carried out for 30 minutes. Subsequently the upper layer was removed, and the same amount of toluene was added again. The same operated was repeated to carry out washing operation. Then, 48% sodium hydroxide aqueous solution was used to adjust the pH of the reaction solution to 11.8. In this case, white turbidity occurred due to the liberated 1-benzyloxycarbonyl-3-methylpiperazine. To the white turbid solution, 40 g of toluene was added, and stirring was carried out for 30 minutes. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70C in temperature, toluene being then distilled away. Ten point three two grams of the obtainedl-benzyloxycarbonyl-3-methylpiperazine was placed in a 10 ml heart flask and distilled in vacuum. When the oil bath reached 145C, the removal by distillation started, and the temperature was raised finally up to 170C. The internal pressure ranged from 40 to 53 Pa, and the temperature at the column top ranged from 131 to 140C. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 99.7 area %. The impurities showed 0.03 area % for benzyl alcohol, 0.12 for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.08 area % for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (for solvent toluene either). Therefore, the total of impurities was 0.23 wt%. Furthermore, the optical purity was 99.4%ee.
Example 15 A 2-liter four-neck flask with a thermometer, condenser and stirrer was charged with 200.4 g (= 2.00 moles) of racemic 2-methylpiperazine, 280.0 g of water and 96.0 g of methanol for perfect dissolution. Then, 300.4 g of 50 wt% D-tartaric acid aqueous solution (150.2 g = 1.000 mole of D-tartaric acid) was added at 40 to 45C, and the temperature was further raised up to 72C, being followed by addition of 120.2 g (= 2.00 moles) of acetic acid and aging at the temperature for 2 hours. The solvent composition was water/methanol = 81.8/18.2 (ratio by weight), and the amount of the solvent based on the racemic 2-methylpiperazine was 2.63 times by weight. Then, cooling was carried out down to 25C, taking 12 hours, and precipitated crystals were collected by filtration. The obtained crystals were dried in vacuum, to obtain 214.8 g (= 0.858 mole) of a diastereomer salt. The optical purity of the salt was 93.9%ee, and the yield of the S-isomer in the obtained salt based on the amount of the S-isomer in the supplied (+/-)-2-methylpiperazine was 83.2%. Subsequently, a 1-liter flask was charged with 380 g of water, and the obtained 214.8 g of crystals {pure (S)-2-methylpiperazine content = 83.4 g} were added. Perfect dissolution was achieved at 80 to 85C, and cooling was carried out down to 15C, taking 12 hours. Precipitated crystals were collected by filtration and dried in vacuum to obtain 187.2 g of a salt. Its optical purity was 99.4%ee, and the yield of the S-isomer in the obtained salt based on the amount of (S)-2-methylpiperazine in the supplied crystals was 89.8%. A 500 ml four-neck flask with a thermometer, condenser and stirrer was charged with 150 g of water, and 185.0 g of (S)-2-methylpiperazine D-tartaric acid salt (= 0.739 mole, optical purity of 2-methylpiperazine = 99.4%ee) obtained before and 69.1 g (= 0.863 mole) of 95% pure calcium hydroxide were added. The slurry was heated up to 70 to 80C, and stirred for 3 hours, then being cooled to room temperature. Subsequently, the non-dissolved salt was filtered away, to obtain the mother liquor. The mother liquor was GC-analyzed, and as a result, it was found that 68.7 g (= 0.686 mole) of optically active 2-methylpiperazine existed in the mother liquor (yield 92.8%). Furthermore, as a result of HPLC analysis, the optical purity of (S)-2-methylpiperazine was 99.4%ee. Then, water was distilled away till about 50 wt% was reached, being followed by addition of 1-butanol, and azeotropic dehydration was carried out till the water content of the system became less than 1 wt%. In a 1-liter four-neck flask, 50.0 g of the (S)-2-methylpiperazine (= 0.499 mole, optical purity 99.4%ee) obtained before was placed, and 440 g of 1-butanol was added for dissolution. The solution was cooled down to 0C, and 92.5 g (= 0.534 mole) of benzyl chlorocarbonate was added dropwise with the liquid temperature kept in a range from 0 to 8C. Then, stirring was carried out at 0C for 2 hours, and 300 g of 1-butanol was distilled away under reduced pressure, being followed by addition of 300 g of water. Subsequently 35% hydrochloric acid water was used to adjust the pH to 1.0, and 220 g of toluene was added, being followed by stirring for 30 minutes. The upper layer was then removed, and the same amount of toluene was added again. The same operation was repeated to carry out washing operation. Subsequently 48% sodium hydroxide aqueous solution was used to adjust the pH of the reaction solution to 12.1. In this case, white turbidity occurred due to liberated 1-benzyloxycarbonyl-3-methylpiperazine. To the white turbid solution, 400 g of toluene was added, and stirring water carried out for 30 minutes. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70C in temperature. Subsequently toluene was distilled away to obtain 88.5 g of a concentrate. Eighty five point .zero grams of the obtained 1-benzyoxycarbonyl-3-methylpiperazine was fed to a thin film distiller (heating surface area 0.02 m2) using a liquid feed pump at 0.6 liter/h. The temperature of the heating medium was 150C, and a low-boiling component was cut at a vacuum degree of 360 Pa, to obtain 82.8 g of a liquid remaining in the distiller. The liquid remaining in the distiller was again fed to the same thin film distiller at 0.6 liter/h using a liquid feed pump. The temperature of the heating medium was 220C, and product distillation was carried out at 87 to 116 Pa in vacuum degree, to obtain 76.1 g of a distillate. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 99.4 liquid chromatography area %. The impurities showed 0.25 liquid chromatography area % for benzyl alcohol, 0.03 liquid chromatography area % for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.02 liquid chromatography area % for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (and 0.08 area % for sol...
With acetic acid; In water; at 15 - 75℃; for 7h;Product distribution / selectivity;
Example 16 A 1-liter four-neck flask with a thermometer, stirrer and condenser was charged with 100.0 g of water and 90.0 g (= 0.600 mole) of D-tartaric acid, and after a homogeneous solution was formed, 200.4 g of an aqueous solution containing 50 wt% of racemic 2-methylpiperazine (pure 2-methylpiperazine content = 1.00 mole) and 36.0 g (= 0.600 mole) of acetic acid were added at room temperature. A homogeneous solution was formed at 70 to 75C, and seed crystals were added at 65C, being followed by aging for 1 hour. Then, cooling was carried out down to 15C, taking 5 hours, being followed by aging at the temperature for 1hour. The obtained slurry was separated into a solid and a liquid, to obtain 172.1 g of a wet cake (pure 2-methylpiperazine content = 44.78 g = 0.447 mole) (optical purity = 92.6%ee, S-isomer yield = 86.1% based on the amount of supplied S-isomer). Then, a 1-liter four-neck flask with a thermometer, stirrer and condenser was charged with 130.0 g of water, and 154.9 g of the obtained cake (pure 2-methylpiperazine content = 40.30 g = 0.402 mole) was added at room temperature. The temperature was raised up to 75 to 85C for dissolution, and seed crystals were added at 70C, being followed by aging for 1 hour, cooling down to 15C taking 5 hours and aging at the temperature for 1 hour. The obtained slurry was separated into a solid and a liquid, to obtain 107.0 g of a wet cake (pure 2-methylpiperazine content = 36.40 g = 0.363 mole) (optical purity = 99.5%ee, S-isomer yield = 90.3% based on the amount of supplied S-isomer). Then, a 1-liter four-neck flask with a thermometer, stirrer and condenser was charged with 300 g of water, and 100.0 g of the obtained wet cake (pure 2-methylpiperazine content = 34.01 g = 0.340 mole) was added. The temperature was raised up to 70C for dissolution, and 34.42 g (0.442 mole, 1.3 molar times) of 95% calcium hydroxide was added. Aging was carried out at 78 to 82C for 3 hours, and solid-liquid separation was carried out to recover (S)-2-methylpiperazine. The 2-methylpiperazine content in the mother liquor was 33.38 g (= 0.333 mole) (recovery rate 98.0%). From the obtained mother liquor, 230 g of water was distilled away, and 340 g of 1-butanol was added, concentration then being carried out at 60 to 70C. In this case, Dean and Stark was installed to return the upper layer of the distillate into the distiller. When the water content in the distiller became 2.1 wt%, concentration was stopped, being followed by cooling down to 0C. The 2-methylpiperazine content of the solution in the distiller was 32.38 g (= 0.323 mole) (recovery rate = 97.0%). To the solution, 58.72 g (= 0.339 mole, 1.05 molar times) of benzyl chlorocarbonate was added dropwise while the dropwise added amount was adjusted to keep the temperature in the distiller at 0 to 10C. Then, the temperature was raised to room temperature, being followed by aging for 2 hours, and concentration under reduced pressure was carried out at 60 to 70C for distilling away 180 g (pure ZMP content = 68.50 g = 0.292 mole, reaction yield 90.5%). Three hundred and eighty grams of toluene was added, and concentration under reduced pressure was carried out at 60 to 70C, for distilling away 340 g. To the concentrate, 200 g of water was added, and 35% hydrochloric acid water was used to adjust the pH to 1.2. Aging was carried out for 30 minutes, and the upper layer was removed. The same operation was repeated further twice, and 48% sodium hydroxide aqueous solution was used to adjust the pH of the reaction solution to 12.0, being followed by addition of 140 g of toluene and stirring for 30 minutes. The lower layer was then removed, and 100 g of water was added, being followed by stirring. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70C, toluene being then distilled away at 1.3 kPa and 80C, to obtain 67.60 g of a concentrate. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 97.2 liquid chromatography area %. The impurities showed 0.27 liquid chromatography area % for benzyl alcohol, 0.02 liquid chromatography area % for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.01 liquid chromatography area % for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (2.44 liquid chromatography area % for solvent toluene). Therefore, the total of impurities was 0.31 liquid chromatography area %.
83.2%
With acetic acid; In methanol; water; at 25 - 72℃; for 14h;Product distribution / selectivity;
Example 15 A 2-liter four-neck flask with a thermometer, condenser and stirrer was charged with 200.4 g (= 2.00 moles) of racemic 2-methylpiperazine, 280.0 g of water and 96.0 g of methanol for perfect dissolution. Then, 300.4 g of 50 wt% D-tartaric acid aqueous solution (150.2 g = 1.000 mole of D-tartaric acid) was added at 40 to 45C, and the temperature was further raised up to 72C, being followed by addition of 120.2 g (= 2.00 moles) of acetic acid and aging at the temperature for 2 hours. The solvent composition was water/methanol = 81.8/18.2 (ratio by weight), and the amount of the solvent based on the racemic 2-methylpiperazine was 2.63 times by weight. Then, cooling was carried out down to 25C, taking 12 hours, and precipitated crystals were collected by filtration. The obtained crystals were dried in vacuum, to obtain 214.8 g (= 0.858 mole) of a diastereomer salt. The optical purity of the salt was 93.9%ee, and the yield of the S-isomer in the obtained salt based on the amount of the S-isomer in the supplied (+/-)-2-methylpiperazine was 83.2%. Subsequently, a 1-liter flask was charged with 380 g of water, and the obtained 214.8 g of crystals {pure (S)-2-methylpiperazine content = 83.4 g} were added. Perfect dissolution was achieved at 80 to 85C, and cooling was carried out down to 15C, taking 12 hours. Precipitated crystals were collected by filtration and dried in vacuum to obtain 187.2 g of a salt. Its optical purity was 99.4%ee, and the yield of the S-isomer in the obtained salt based on the amount of (S)-2-methylpiperazine in the supplied crystals was 89.8%. A 500 ml four-neck flask with a thermometer, condenser and stirrer was charged with 150 g of water, and 185.0 g of (S)-2-methylpiperazine D-tartaric acid salt (= 0.739 mole, optical purity of 2-methylpiperazine = 99.4%ee) obtained before and 69.1 g (= 0.863 mole) of 95% pure calcium hydroxide were added. The slurry was heated up to 70 to 80C, and stirred for 3 hours, then being cooled to room temperature. Subsequently, the non-dissolved salt was filtered away, to obtain the mother liquor. The mother liquor was GC-analyzed, and as a result, it was found that 68.7 g (= 0.686 mole) of optically active 2-methylpiperazine existed in the mother liquor (yield 92.8%). Furthermore, as a result of HPLC analysis, the optical purity of (S)-2-methylpiperazine was 99.4%ee. Then, water was distilled away till about 50 wt% was reached, being followed by addition of 1-butanol, and azeotropic dehydration was carried out till the water content of the system became less than 1 wt%. In a 1-liter four-neck flask, 50.0 g of the (S)-2-methylpiperazine (= 0.499 mole, optical purity 99.4%ee) obtained before was placed, and 440 g of 1-butanol was added for dissolution. The solution was cooled down to 0C, and 92.5 g (= 0.534 mole) of benzyl chlorocarbonate was added dropwise with the liquid temperature kept in a range from 0 to 8C. Then, stirring was carried out at 0C for 2 hours, and 300 g of 1-butanol was distilled away under reduced pressure, being followed by addition of 300 g of water. Subsequently 35% hydrochloric acid water was used to adjust the pH to 1.0, and 220 g of toluene was added, being followed by stirring for 30 minutes. The upper layer was then removed, and the same amount of toluene was added again. The same operation was repeated to carry out washing operation. Subsequently 48% sodium hydroxide aqueous solution was used to adjust the pH of the reaction solution to 12.1. In this case, white turbidity occurred due to liberated 1-benzyloxycarbonyl-3-methylpiperazine. To the white turbid solution, 400 g of toluene was added, and stirring water carried out for 30 minutes. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70C in temperature. Subsequently toluene was distilled away to obtain 88.5 g of a concentrate. Eighty five point .zero grams of the obtained 1-benzyoxycarbonyl-3-methylpiperazine was fed to a thin film distiller (heating surface area 0.02 m2) using a liquid feed pump at 0.6 liter/h. The temperature of the heating medium was 150C, and a low-boiling component was cut at a vacuum degree of 360 Pa, to obtain 82.8 g of a liquid remaining in the distiller. The liquid remaining in the distiller was again fed to the same thin film distiller at 0.6 liter/h using a liquid feed pump. The temperature of the heating medium was 220C, and product distillation was carried out at 87 to 116 Pa in vacuum degree, to obtain 76.1 g of a distillate. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 99.4 liquid chromatography area %. The impurities showed 0.25 liquid chromatography area % for benzyl alcohol, 0.03 liquid chromatography area % for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.02 liquid chromatography area % for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (and 0.08 area % for sol...
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 17h;
To a solution of 2-chloronicotinonitrile (3.0 g, 21.7 mmol) and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (2.17 g, 21.7 mmol) in DMF (10 mL) was added K2C03 (9.0 g, 65.1 mmol). The mixture was stirred at 120 C for 17 h. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na2504), filtered, and concentrated in vacuo to afford (S)-2-(3-methylpiperazin-1-yl)nicotinonitrile (3.03 g, 80%) as yellow oil. ESI-MS (EI+, m/z: 203 [M+H].
64%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In toluene; at 100℃;
Example 41 GENERAL PROCEDURE: PALLADIUM CATALYZED COUPLING TO HETEROARYL CHLORIDE; 2-Chloro-nicotinonitrile (1.0 mmol), (S) -2-methyl piperazine (1.5 mmol), sodium tert- butoxide (1.5 mmol) and tris (dibenzylideneacetone)-dipalladium (0) (0.04 mmol) were added to a screw cap vial. 2, 8, 9-Triisobutyl-2,5, 8, 9-tetraaza-1-phospha-bicyclo [3.3. 3] undecane (0. 08 mmol) was dissolved in toluene (5 mL) and this solution was added to the other reagents. The reaction mixture was stirred at 100 C overnight. The solution was diluted with dichloromethane and washed with water. The organic phase was dried, filtered and concentrated, then purified by flash chromatography in 10% (2M ammonia in methanol) in dichloromethane to yield the desired product.
64%
With sodium t-butanolate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane;tris-(dibenzylideneacetone)dipalladium(0); In dichloromethane; toluene; at 100℃;
EXAMPLE 9 General Procedure: Palladium Catalyzed Coupling to Heteroaryl Chloride 2-Chloro-nicotinonitrile (1.0 mmol), (S)-2-methyl piperazine (1.5 mmol), sodium tert-butoxide (1.5 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (0.04 mmol) were added to a screw cap vial. 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.08 mmol) was dissolved in toluene (5 mL) and this solution was added to the other reagents. The reaction mixture was stirred at 100 C. overnight. The solution was diluted with dichloromethane and washed with water. The organic phase was dried, filtered and concentrated, then purified by flash chromatography in 10% (2M ammonia in methanol) in dichloromethane to yield the desired product. In this manner the following compounds were synthesized: Example Structure Name Yield 9.1 2-[(3S)-3-methylpiperazin-1-yl]nicotinonitrile 64%1H 1.03(d, J=6.3 Hz, 3H); 1.73(s, broad, 1H); 2.59(dd, J=12.9, 10.2 Hz, 1H); 2.94(m, NMR 4H); 4.16(m, 2H); 6.64(dd, J=7.8, 4.8 Hz, 1H); 7.66(dd, J=7.8, 2.1 Hz, 1H); 8.23(dd, J=4.8, 2.1 Hz, 1H).
Example 39 GENERAL PROCEDURE: NUCLEOPHILIC DISPLACEMENT WITH 2-CHLORO-3- NITRO-PYRIDINE; Piperazine (2-5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol) were dissolved in DMF or acetonitrile (2-3 mL) and stirred for 5 min at room temperature. A slight exothermic was observed shortly after addition of the solvent. When TLC analysis showed that the reaction was complete, the mixture was diluted with dichloromethane, and washed with water. The organic layer was dried, filtered and concentrated, then chromatographed in 10% methanol in dichloromethane to yield the desired product.
92%
In N,N-dimethyl-formamide; at 20℃; for 0.0833333h;
EXAMPLE 6 General Procedure: Nucleophilic Displacement with 2-Chloro-3-NitroPyridine Piperazine (2-5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol) were dissolved in DMF or acetonitrile (2-3 mL) and stirred for 5 min at room temperature. A slight exotherm was observed shortly after addition of the solvent. When TLC analysis showed that the reaction was complete, the mixture was diluted with dichloromethane, and washed with water. The organic layer was dried, filtered and concentrated, then chromatographed in 10% methanol in dichloromethane to yield the desired product.; In this manner the following compounds were synthesized: Example Structure Name Yield 6.1 (3S)-3-methyl-1-(3-nitropyridin-2-yl) piperazine 92%1H 1.11(d, J=6.3 Hz, 3H); 2.74(dd, J=12.8, 10.4 Hz, 1H); 2.99(m, 4H); 3.72(m, 2H); NMR 6.74(dd, J=8.1, 4.5 Hz, 1H); 8.14(dd, J=8.1, 1.8 Hz, 1H); 8.34(dd, J=4.5, 1.8 Hz, 1H).
With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 16h;
To a solution of <strong>[74879-18-8](S)-2-methylpiperazine</strong> (10 g, 100 mmol, eq) in EtOH (200 ml_) was added DIPEA (43.58 ml_, 250 mmol, 2.5 eq) and BOC20 (21.8 ml_, 100 mmol, 1 eq) at RT, then the reaction mixture was continued for 16 h. TLC analysis indicated formation of a less polar spot. The reaction mixture was concentrated to crude compound, which was diluted with water and extracted with EtOAc (3x100 ml_). The combined organic layer was dried over Na2S04 then concentrated to give (S)-tert-butyl 3-methylpiperazine- 1 -carboxylate (18 g, 90%) as a colorless oil.
90%
With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 16h;
To a solution of compound 1 (1 Og, 100mmol, 1 eq) in EtOH (200ml) was added DIPEA (43.58ml_, 250mmol, 2.5eq) and B0C2O (21.8ml_, l OOmmol, 1 eq) at RT, then the reaction was continued for 16h. TLC analysis indicated formation of a less polar spot. The reaction mixture was concentrated to crude compound, which is diluted with water and extracted with EtOAc (3x100ml_). The combined organic layer was dried over Na2S04 then concentrated to give compound 2 (18g, 90%) as a colorless oil.
84%
In dichloromethane; at 20℃; for 4h;
To a solution of (S)-methylpiperazine (400 mg) in dichloromethane (20 mL) at 0 C. was added di-tert-butyl dicarbonate (871 mg). The reaction was stirred at room temperature for 4 h and then quenched with water (20 mL) and extracted into dichloromethane (2*40 mL). The combined organics were washed with saturated aqueous brine solution (40 mL), dried (MgSO4) and concentrated to give (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid (669 mg, 84%).
84%
In dichloromethane; at 0 - 20℃; for 4h;
To a solution of (S)-methylpiperazine (400 mg) in dichloromethane (20 mL) at0 C was added di-tert-butyl dicarbonate (871 mg). The reaction was stirred at room <n="187"/>temperature for 4 h and then quenched with water (20 mL) and extracted into dichloromethane (2 x 40 mL). The combined organics were washed with saturated aqueous brine solution (40 mL), dried (MgSO4) and concentrated to give (S)-3-methyl-piperazine-l- carboxylic acid tert-butyl ester as a white solid (669 mg, 84%).
80%
With triethylamine; In dichloromethane; for 5h;
Step B tert-Butyl (3S)-3-methylpiperazine-1-carboxylate To a solution of (2S)-2-methylpiperazine (20.0 g, 0.200 mol) in methylene chloride (300 mL) and triethylamine (20.4 g, 0.202 mol) was added dropwise a solution of di-tert-butyl dicarbonate (44.0 g, 0.202 mol) in CH2Cl2 (100 mL) over 5 hrs. The mixture was washed with water, brine, and then dried over MgSO4 and concentrated. Column chromatography on silica (10-20% MeOH in EtOAc) afforded 32.0 g (80%) of the title compound as an oil. Step C tert-Butyl (3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazine-1-carboxylate
76.4%
With hydrogenchloride; In methanol; water; at 15 - 30℃; for 18h;
Example 5 (0326) [0227] Compound 154 was prepared according to the reaction scheme in Figures 3 and 4. (0327) [0228] In a first step, compound 40 was prepared from compound 30 as follows: (0328) (0329) 30 40 (0330) [0229] Water (500 g, 5 w/w%) was charged to a reaction flask. Compound 30 (2- methylpiperazine) (100 g, 998.4 mmol, 1 eq.) was charged to the reaction flask with agitation. HC1 (36% aqueous, 102.1 g, 1008 mmol, 1.01 eq.) and methanol (200 g) were charged to the reaction flask with agitation. A solution of Boc20 (222 g, 1008 mmol, 1.01 eq.) in methanol (200 g) was added dropwise to the reaction flask at 15 to 25 C followed by stirring for 18 hours at 20 to 30C. The flask contents were evaporated to dryness in vacuo at 40 to 50C to form a residue. Water (500 g) was added to the residue and the mixture was stirred for 1 hours. The mixture was filtered and the collected solids were washed with water (50 g). The aqueous filtrate was extracted with ethylacetate (500 mL). The extracted aqueous phase was adjusted to a pH in excess of 12 with 30% NaOH and was then extracted with ethylacetate (500 mL) three times. The organic phase was washed with brine (500 g) twice and was then dried with anhydrous Na2S04. The dried mixture was filtered and the collected solids were rinsed with ethylacetate (100 mL). The filtrate was concentrated to dryness in vacuo at 50 to 60C and further concentrated under high vacuum (5 mm Hg) at 65 to 75C for 3 hours to yield compound 40 (tert-butyl 3-methylpiperazine-l-carboxylate). The purity of compound 40 was 97.7 area%, the assay was 95.9% and the yield was 76.4%.
49%
In dichloromethane; at 0 - 20℃;
<strong>[74879-18-8](S)-2-methylpiperazine</strong> (5.00 g, 49.9 mmol) was dissolved in DCM (150 mL). A solution of boc anhydride (5.47 g, 25.0 mmol) in DCM (50 mL) was added dropwise at 0 C. The reaction mixture was stirred at rt for 2 h. The solution was filtered and concentrated under reduced pressure. Water (100 mL) was added to the residue and it was filtered again. The filtrate was saturated with K2CO3 and extracted with Et2O (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 4.92 g title compound (49%) as a solid. 1H NMR (300 MHz, CDCl3) delta ppm 1.03 (d, J=6.3 Hz, 3H) 1.45 (s, 9H) 1.53 (br. s, 1H) 2.38 (t, J=11.8 Hz, 1H) 2.65-2.72 (m, 1H) 2.74-2.76 (m, 2H) 2.92-2.95 (m, 1H) 3.92 (br. s, 2H).
With triethylamine; In methanol; for 17h;
Triethylamine (2.85 ml) was added to a solution of (S)-2-methyl piperazine (1 g) in methanol (25 ml) followed by portion wise addition of BOC anhydride (2.18 g). The reaction mixture was stirred for 17 h, concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was dried (MgSO4), and then concentrated in vacuo. The residue was purified by chromatography (silica, ethyl acetate as eluent, then 90:10:1 mixture of ethyl acetate: methanol: ammonia) to give the sub-title compound (1.3 g). 1H NMR (CDCl3) delta 4.03-3.85 (2H, m), 2.95 (IH, d), 2.86-2.65 (3H, m), 2.5-2.3 (IH, m), 1.48 (9H, s) and 1.05 (3H, d).
With triethylamine; In hexane; dichloromethane; ethyl acetate;
Step 1: 3-(S)-Methyl-piperazine-1-carboxylic Acid Tert-Butyl Ester Triethylamine (3 g, 4.2 mL, 30 mmol) was added to a solution of 2-(S)-methyl piperazine (2 g, 20 mmol) in dichloromethane (40 mL) followed by di-tert-butyl-dicarbonate (4.8 g, 22 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The crude product was purified using a short plug of silica gel using hexane/ethyl acetate (1:1). 1H-NMR (CDCl3) delta: 1.03 (3H, d), 1.45 (9H, s), 1.65 (1H, s), 2.35-2.42 (1H, m), 2.66-2.80 (3H, m), 2.92-2.95 (1H, m), 3.92 (2H, br s). ESI-MS m/z: 201(M+1).
With triethylamine; In methanol; for 17h;
Triethylamine (2.85 ml) was added to a solution of (S)-2-methyl piperazine (1 g) in methanol (25 ml), this was followed by portionwise addition of BOC anhydride (2.18 g). The reaction mixture was stirred for 17 h, then concentrated under reduced pressure. Water was added to the residue and extracted EtOAc (×3), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica (eluent EtOAc, then 9:1:1 EtOAc:MeOH:NH3) to give the sub-title compound as a colourless oil, yield 1.3 g.1H NMR CDCl3: delta 4.04-3.82 (2H, m), 2.95 (1H, d), 2.81-2.66 (3H, m), 2.48-2.32 (1H, m), 1.47 (9H, s), 1.05 (3H, d).
562 mg
With triethylamine; In dichloromethane; at 0℃; for 2h;
Description 146(S)-tert-butyl 3-methylpiperazine-1-carboxylate (1)146)NHBocTo a solution of <strong>[74879-18-8](S)-2-methylpiperazine</strong> (500 mg) in DCM (5 mL) was added Et3N (1010 mg) and(Boc)20 (1198 mg) in DCM (3 mL) dropwise. The mixture was stirred at 0C for 2 hours. DCM(10 mL), water (5 mL) and 30% NaHSO4 (10 mL) aqueous solution were added to the reactionmixture. The resulted mixture was stirred for 10 mm, and to the aqueous layer was added saturatedNa2CO3 solution until pH = 8, extracted with isopropyl alcohol: chlorofonn1: 3 (5 x20 mL). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to afford the title compound (562 mg) as pale yellow oil, MS (ESI): C10H20N202 requires 200; found 201 [M+H].
With triethylamine; In hexane; dichloromethane;
Step 1 3-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester Triethylamine (3 g, 4.2 mL, 30 mmol) was added to a solution of 2-(S)-methyl piperazine (2 g, 20 mmol) in dichloromethane (40 mL) followed by di-tert-butyl-dicarbonate (4.8 g, 22 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The crude product was purified using a short plug of silica gel using hexane/ethyl acetate (1:1). 1H-NMR (CDCl3) delta: 1.03 (3H, d), 1.45 (9H, s), 1.65 (1H, s), 2.35-2.42 (1H, m), 2.66-2.80 (3H, m), 2.92-2.95 (1H, m), 3.92 (2H, br s). ESI-MS m/z: 201 (M+1).
2-methylpiperazine-1,4-dicarboxylic acid dibenzyl ester[ No CAS ]
[ 612493-87-5 ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In methanol; water; at 0 - 10℃; for 2.5h;
To a solution of S-2-methylpiperazine (100 g) in methanol (1200 mL) and water (400 mL) was charged 180 mL acetic acid. Benzyl chloroformate was added over a period of 90 min at about 0-10 C. After agitation at about 0-10 C. for 1 h, the reaction mixture was diluted with water and mixture was concentrated to remove methanol. HPLC analysis showed that the ratio of mono-acylation vs. di-acylation products was about 98/2. The resulting aqueous mixture was washed with toluene (300 mL). The aqueous layer was basified with 25% NaOH (690 mL) and extracted with toluene (700 mL). The toluene layer was concentrated and residual solid sodium acetate was removed by filtration. HPLC analysis showed that the concentrate contained 208 g product (89% yield). The product thus prepared is very clean and can be used in the next step without further purification. HPLC analysis showed that the sample contained about 0.5% regioisomer (1-benzyloxycarbonyl-2-methylpiperazine). Pure S-4-benzyloxycarbonyl-2-methylpiperazine can be obtained by vacuum distillation (clear oil, b.p. 136 C./1 mm). 1H NMR (CDCl3): 7.31 (m, 5H), 5.09 (m, 2H), 3.98 (m, 2H), 2.84 (m, 4H), 2.47 (m, 1H), 1.78 (br s, 1H), 1.00 (d, J=5.5 Hz, 3H).
95.i i
i (S)-2-(3-Methylpiperazin-1-yl)-N-(quinolin-5-yl)acetamide to The subtitle compound was prepared from 2-chloro-N-(quinolin-5-yl)acetamide (1 g) (J Indian Chem Soc, 1940, 17, 619-621) and (S)-2-methylpiperazine (0.5 g) by the method of Example 58 step (i) as a white solid. Yield: 1.4 g MS: APCI(+ve) 285 (M+1)
Step l; 3-(5)-Methyl-l-(5-trifluoromethyl-pyridin-2-yl)-piperazine:; 2-Bromo-5-trifluoromethyl-pyridine (1.06 g, 4.69 mmol), (5)-2-methylpiperazine (1.03 g, 10.28 mmol) and triethylamine (1.5 mL, 10.76 mmol) were stirred in toluene (10 mL) at 110 0C for 26 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with water and brine. The organic layer was dried (MgSC>4), filtered and concentrated. The crude mixture was purified by automated silica gel flash column chromatography (gradient eluent 0-20% MeOH/dichloromethane) to afford 3-(S)-methyl-l-(5-trifluoromethyI-pyridin-2-yl)- piperazine (926 mg, 81 %) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.38 (s, IH), 7.62 (dd, IH), 7.63 (d, IH), 4.29-4.20 (m, 2H), 3.16-3.12 (m, IH), 3.02-2.85 (m, 3H), 2.64-2.52 (m, 2H), 1.18 (d, 3H).
With caesium carbonate; johnphos;palladium diacetate; In 1,4-dioxane; water; for 4h;Heating / reflux;
A mixture of 2-(4-bromophenyl)-5-methylpyrimidine 78 (250mg, 1.008mmol), palladium acetate (50mg), cesium carbonate (400mgf1.23mmol), (S)-2-methyl piperazine(200mg, 2mmol) and 2-Di-t-butylphosphino)-biphenyl (50mg, 0.167mmol) was stirred in dioxane:water (10ml,v/v 5:1 ) at reflux temperature for 4 hours. The reaction was cooled.diluted with MeCI2 (100ml) and H2O (50ml). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated. The residue was purified by chromatography eluting with 100% EtOAc then with 10% v/v MeOHZEtOAcZIVJH4OH yielding product 79 as a white solid. (220mg.81%) ESMS (MH, 269).
81%
With caesium carbonate; johnphos;palladium diacetate; In 1,4-dioxane; water; for 4h;Heating / reflux;
A mixture of 2-(4-bromophenyl)-5-methylpyrimidine 78 (250mg, 1.008mmol), palladium acetate (50mg), cesium carbonate (400mg,1.23mmol), (S)-2-methyl piperazine(200mg, 2mmol) and 2-Di-t-butylphosphino)-biphenyl (50mg, 0.167mmol) <n="213"/>was stirred in dioxane:water (10ml,v/v 5:1 ) at reflux temperature for 4 hours. The reaction was cooled, diluted with MeCI2 (100ml) and H2O (50ml). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated. The residue was purified by chromatography eluting with 100% EtOAc then with 10% v/v MeOH/EtOAc/NH4OH yielding product 79 as a white solid. (220mg.81%) ESMS (MH, 269).
With sodium t-butanolate;dichlorobis(tri-O-tolylphosphine)palladium; In toluene; at 100℃; for 2h;
To (S)-2-methyl piperazine (0.150 g, 1.5 mmol) was added 4-bromobenzotrifluoride (0.225g, 1.0 mmol), dichloro-bis(tri-o-tolyphosphine) palladium (II) (0.236 g, 0.3mmol), and sodium t-butoxide (0.144 g, 1.5 mmol), and toluene (2 mL) sequentially. After nitrogen was bubbled through the mixture for 15 minutes, the reaction was heated to lOO'C. The reaction was stirred at 1000C for 2 hr. The reaction was filtered through celite and concentrated under reduced pressure. The residue was then purified on a 1000 micron <n="158"/>preparative thin layer chromatography plate eluting with 5% MeOH in dichloromethane to yield the title compound as an oil. IH NMR (500 MHz, CDCl3) delta 7.5 (d, 2H, J=8.7Hz), 6.95 (d, 2H, J = 8.7 Hz), 3.71 (d, 2H, J=IOHz), 3.20 (m, IH), 3.04 (m, 2H), 2.85 (m, 1H),2.48 (m, IH), 1.24 (d, 3H, J=7.2Hz). LC/MS 247 (M+l); HPLC 2.41 min
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 80℃; for 2.5h;
Example 189: Synthesis of 4-Chloro-6-[2-((R)-3-methyl-piperazin-l-yl)-benzyl amino]-4a,8a-dihydro-2H-phthalazin-l-one; 2-((R)-3-Methyl-piperazin-l-yl)-benzonitrile; A mixture 2-bromobenzonitrile (1.0 g, 5.494 mmol), <strong>[74879-18-8](S)-(+)-2-methylpiperazine</strong>(0.60 g, 5.99 mmol), Pd2(dba)3 (0.503 g, 0.549 mmol), rac-BINAP (1.026 g, 1.648 mmol) and NaO'Bu (2.11 g, 21.976 mmol) in DMA (27 mL) was heated at 8O0C for 2.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (EtOAc/MeOH) afforded 2-((R)-3 -methyl-piperazin- 1 -yl)-benzonitrile (540 mg) as a white solid. 1H (400 MHz, d6-DMSO) delta: ppm; m/z (M+l) 202.21.
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 1h;
(S)-2-Methylpiperazine (CAS No 74879-18-8) (420mg) is added to a solution ofIntermediate 7 (1g) in a mixture of NMP (10ml) and TEA (0.5 ml). The mixture is stirred for 1h at room temperature and then added to water (40ml). The mixture is stirred for 30 min, then the product is collected by filtration and washed with water (2 x 20ml) to give the title compound as colourless solid (H Og1 92 %). LCMS 402/404 [M+H]+, RT 2.64 mins (pH 5.8). 1 H NMR 300 MHz (d6-DMSO) (delta ppm): 9.65 (1 H, br s), 7.95 (1 H, m), 7.85 (1 H, d), <n="38"/>7.68 (1 H, dd), 4.75 (2H, m), 3.00-3.15 (2H, m), 2.70-2.82 (3H, m), 2.50 (1H, br s), 1.23 (9H, s), 1.07 (3H1 d)
A mixture of Intermediate 41 (0.3g), (2S)-2-methylpiperazine (CAS No 74879-18-8) (0.1g) and TEA (0.12g) in methanol (20.OmL) is heated at 650C for 4 hours. The solvent is evaporated in vacuo. Purification of the residue by column chromatography on silica, eluting with DCM / methanol (95:5), affords the title compound as a white solid (0.26g, 73%). LCMS 362/364 [M+H]+, RT 2.24 mins (pH 5.8). 1H NMR 300 MHz (CDCI3) (delta ppm):8.15 (1 H, d), 7.60 (1 H, dd), 7.40 (1H, d), 4.85 (4H, m) 3.15 (2H, m), 2.95 (2H, m), 2.75(1 H, t), 1.95 (3H, d).
With triethylamine; In N,N-dimethyl-formamide; at 20.0℃; for 14.0h;
Triethylamine (4.13 g, 3 niL, 40.8 mmol, 4 eq) is added to a solution of 6-chloro- nicotinonitrile (1.38 g, 10 mmol, leq), (S)-2-methyl- piperazine (1.0Og, 10 mmol, leq) in DMF (15 niL), and the resulting solution is stirred at rt for 14 h. A white precipitate of triethylamine hydrochloride forms in the course of the reaction. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The solid is further dried under high vacuum to yield the desired product as a white solid (1.4 g, 69%). 1H NMR (400 MHz, CHLOROFORM-cf) delta ppm 8.38 (s, 1 H), 7.58 (d, J=9.60 Hz, 1 H), 6.59 (d, J=9.09 Hz, 1 H), 4.19 - 4.31 (m, 2 H), 3.08 - 3.15 (m, 1 H), 2.92 - 3.04 (m, 1 H), 2.81 - 2.91 (m, 2 H), 2.57 - 2.65 (m, 1 H), 1.15 (d. J=6.32 Hz, 3 H).
67%
With potassium carbonate; In N,N-dimethyl acetamide; at 60.0℃; for 2.0h;
To a stirred solution of (2S)-2-methylpiperazine (0.30 g, 2.1 mmol) in DMA (6 mL), 6-chloropyridine-3-carbonitrile (0.29 g, 2.3 mmol) and K2C03 were added. The resultantreaction mixture was heated to 60 C for 2 h (TLC indicated complete consumption ofstarting material). The reaction mixture was diluted with cold water (20 mL) and extractedwith EtOAc (3 x 25 mL). The combined organic extracts were washed with cold water (20mL) and brine (2 x 20 mL). The organic layer was separated, dried over Na2S04 andconcentrated under reduced pressure to give the crude residue which was purified by columnchromatography (100-200 silica gel, 10 g, 10% MeOH-DCM) to furnish 6-[(3S)-3-methylpiperazin-1-yl]pyridine-3-carbonitrile (0.29 g, 67%) as an off-white solid.LCMS: m/z: 203.4 [M+Ht.
4-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
To a suspension of 2-(S)-methylpiperazine (2.65 g, 26.5 mmol) and K2CO3 (4.0 g, 29 mmol) in dry DMSO (50 ML) was slowly added <strong>[55304-75-1]2,6-dichloro-3-trifluoromethylpyridine</strong> (5.70 g, 26.4 mmol).The reaction mixture was stirred at room temperature over night, filtered, diluted with water (ca 1 L) and extracted twice with EtOAc (100 ML).The solvent from the combined dried (MgSO4) organic phases was evaporated at reduced pressure to give a yellow oil (7.4 g).This material was dissolved in MeOH (100 ML), BOC anhydride (6.0 g, 27.5 mmol) was added in one portion and the reaction mixture was stirred at room temperature for two hours.Excess BOC anhydride was quenched with pyridine (3 ML) and the mixture was left at room temperature over night.The solvent was removed at reduced pressure and the resulting oil was chromatographed on a column of silica (60*110 mm) with hexane/EtOAc (95:5, 1 L, followed by 90:10, 1 L and 80:20).Evaporation at reduced pressure of the pure fractions yielded a colorless oil (8.05 g, 80%) that solidified to a white solid over night.Purity 97% (HPLC); mp 86 C. Fragmenting MS analysis supports the stated structure. HRMS m/z calcd for C16H21ClF3N3O2 (M)+ 379.1274, found 379.1286.
With triethylamine; In isopropyl alcohol; at 80℃; for 0.0833333h;Microwave irradiation;
C. Preparation of (S)-5-bromo-4-(3-methylpiperazin-1-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine. To a mixture of pyrrolopyrimidine from step B (76 mg, 0.2 mmol) and (S)-2-methylpiperazine (21 mg, 0.2 mmol) in isopropanol (2 ml) was added triethylamine (0.11 ml, 0.8 mmol). The mixture was heated at 80 C. for 5 mins via microwave and concentrated under vacuum to give crude (S)-5-bromo-4-(3-methylpiperazin-1-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg, 0.15 mmol, 75%) which was used directly for the next step. MS (ES+) [M+H]+=437.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 25.0℃; for 2.0h;
To l,4-dichloropyrido[3,4-d]pyridazine 3 (0.500 g, 2.50 mmol) in NMP (2.5 ml) was added (S)-2-methylpiperazine (0.300 g, 3.00 mmol). The reaction was stirred at 25C for 2 h. After one hour reaction contents were diluted with water (20 X) and extracted with 10% MeOH in CH2Cl2 (3 x 25 mL). The combined organics were dried with Na2SO4 and <n="43"/>concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 5% MeOH in CH2Cl2) afforded (S)-I -chloro-4-(3-methylpiperazin-l-yl)pyrido[3,4-d]pyridazine 4 plus 10-15% substitution at the 4-position. 1H NMR (CDCl3) delta 9.48 (s, IH), 9.03 (d, J= 5.5 Hz, IH), 7.94 (d, J= 5.5 Hz, IH) 3.96 (m, 2 H), 3.11-3.88 (m, 5 H), 2.93 (dd, J= 12.8, 10.4, IH). MS (calc'd) 263.1 (M+H, found) 264.1.
To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (1.0 g, 6.3 mMol) in dimethylsulfoxide (7 mL) was added sodium azide (0.45 g, 6.9 mMol). After stirring for 2 h at 20 C. diisopropylethylamine (0.81 g, 6.3 mMol, 1.1 mL) was added to the reaction mixture followed by S-2-methylpiperazine (0.95 g, 9.5 mMol). The reaction mixture stirred at 60 C. for 10 h then 20 C. for an additional 12 h at which point it was diluted with ethyl acetate (50 mL), washed with 1N sodium hydroxide solution (20 mL) and water (2×20 mL). The organic layer was dried (MgSO4), evaporated and the residue dissolved in dichloromethane (25 mL) and treated with di-t-butyldicarbonate (1.5 g, 7.1 mMol). After stirring for 16 h at 20 C. the solvent was evaporated and the residue was chromatographed on silica gel eluted with 75% hexanes in ethyl acetate to provide the product as a yellow gum (2.2 g, 96%). 1H-NMR (CDCl3), δ=7.42 (dd, 1H, J=8.2 Hz, J=8.2 Hz), 7.0 (d, 1H, J=8.2 Hz), 6.95 (d, 1H, J=8.2 Hz), 4.28 (bm, 1H), 3.88 (bd, 1H, J=13.3 Hz), 3.00 (m, 5H), 1.48 (s, 9H), 1.22 (d, 3H, J=6.8 Hz). LC/MS (Method A), rt=2.05 mins., purity=89.8%, calculated mass=362, [M+H-C5H9O2]+=263.
Example 68 (3S)-1-[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methyl}-3-methylpiperazine To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) was added (2S)-2-methylpiperazine (270 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (230 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (111 mg, yield 38%) as a colorless amorphous solid. MS:549(MH+). 1H NMR (300 MHz, CDCl3) 50.98 - 1.03 (2 H, m), 1.05 (3 H, d, J=6.2 Hz), 1.29 - 1.49 (5 H, m), 1.52 - 1.70 (3 H, m), 1.82 - 1.97 (2 H, m), 2.05 - 2.15 (2 H, m), 2.36 - 2.49 (1 H, m), 2.66 - 2.79 (2 H, m), 2.81 - 3.05 (3 H, m), 3.19 - 3.36 (2 H, m), 3.40 - 3.50 (2 H, m), 3.84 - 4.00 (2 H, m), 4.12 - 4.23 (1 H, m), 6.15 (1 H, t, J=3.0 Hz), 6.63 (1 H, dd, J=2.4, 3.5 Hz), 7.40 (2 H, d, J=8.3 Hz), 7.44 - 7.50 (1 H, m), 7.52 - 7.63 (1 H, m), 7.75 - 7.88 (2 H, m), 8.29 (1 H, d, J=1.5 Hz), 9.22 (1 H, brs).
[(2-methylpiperazinium(2+))]0.5[Zn5(2-hydroxyl(phosphono)acetate(2-))(2-hydroxyl(phosphono)acetate(3-))3(water)2]*2water[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
In water High Pressure; heating mixt. of zinc compd., acetic acid deriv., methylpiperazine and water at 160°C for 120 h, final pH were 4.09; isolation of ppt., rinsing with water under ultrasonic conditions, elem.anal.;
Alternative preparation of 3-[((2S)-2-Methyl-4-[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinyl)carbonyl]pyrazolo[1,5-a]pyrimidine: Example 2aPyrazolo[1,5-a]pyrimidine-3-carboxylic acid (11.73 g, 71.9 mmol) was suspended in thionyl chloride (36 mL, 493 mmol) and heated at 60 C. for 2 h. Formation of the acyl chloride was monitored as follows: a sample of the reaction mixture was evaporated and added to MeOH and formation of the corresponding methyl ester was detected by UPLC. Then thionyl chloride was removed under reduced pressure to obtain pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (14 g) as a yellow solid.(2S)-2-methylpiperazine (6 g, 59.9 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled down to 0 C., aqueous sodium hydroxide (3M, 39.9 mL, 120 mmol) was added and stirred for 10 min. Then 4-(trifluoromethyl)benzenesulfonyl chloride (16.12 g, 65.9 mmol) (dissolved in 50 ml of THF) was added drop-wise, stirring the reaction mixture for 1 h. THF was removed under reduced pressure, the aqueous phase was diluted with water (200 ml) and extracted with DCM (2×300 ml). The organic layer was concentrated under reduced pressure and the oily residue was suspended with HCl 1M (200 ml) and washed with DCM in order to extract impurities. NaOH 3M was added to the aqueous layer to reach pH 10 then the mixture was diluted with THF (200 ml), the mixture was cooled down to 0 C.The pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (14 g) was suspended in THF (80 ml) and added portion-wise to the above mixture, maintaining the pH>9 by adding NaOH 3M, and then the mixture was stirred overnight. THF was removed from the mixture under reduced pressure and the resulting suspension was extracted with DCM (2×300 ml). The organic layer was washed with HCl 0.1 M, dried over Na2SO4 and concentrated to dryness to obtain the crude material (21.7 g) as foam. The crude material was re-dissolved in DCM (100 ml) and evaporated to minimum volume to obtain an oily residue, ethyl ether was added (80 ml) with stirring. A solid crashed out from the solution and was recovered by filtration, washing with ethyl ether before drying to give the title compound (20.06 g).m/z (API-ES) 454 [M+H]+ 1H NMR (400 MHz, CDCl3) delta ppm 1.48 (d, J=7.2 Hz, 3H), 2.56 (td, J=11.6, 3.2 Hz, 1H), 2.69 (dd, J=11.6, 3.6 Hz, 1H), 3.50 (m, 1H), 3.64 (d, J=11.6 Hz, 1H), 3.82 (d, J=11.2 Hz, 1H), 4.25 (m, 1H), 4.78 (m, 1H), 6.97 (dd, J=7.2, 4.0 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 8.39 (s, 1H), 8.59 (dd, J=4.0, 1.6 Hz, 1H), 8.73 (dd, J=7.2, 1.6 Hz, 1H).
With sodium hydroxide; In tetrahydrofuran; at 0℃; for 1.16667h;
(2S)-2-methylpiperazine (15 g, 150 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled down to 0 C. Sodium hydroxide (150 mL, 449 mmol) was added, then 4-(trifluoromethyl)benzenesulfonyl chloride (40 g, 164 mmol) (dissolved in 200 ml THF) was added dropwise and the resulting mixture was stirred for 1 h. Further 4-(trifluoromethyl)benzenesulfonyl chloride (0.06 eq, 2.2 g) was added and mixture stirred for 10 min. The mixture was diluted with DCM (500 ml) and water (500 ml) and stirred for 5 min. The phases were separated, the aqueous layer was extracted with DCM (1000 ml) and the organic phases concentrated under reduced pressure. The residue was taken-up with 1 M HCl (500 ml) and washed with DCM in order to extracted impurities. The aqueous phase was basified to pH=9 with NaOH 3M, extracted with DCM (3×500 ml) and the combined organic phases dried over Na2SO4 before the solvent was removed under reduced pressure to give the title compound (30 g).m/z (API-ES) 309 [M+H]+ 1H NMR (400 MHz, CDCl3) delta ppm 1.06 (d, J=7.2 Hz, 3H), 1.94 (t, J=10.4 Hz, 1H), (td, J=11.2, 4.0 Hz, 1H), 2.88-3.07 (m, 3H), 3.66 (m, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H).
With sodium hydroxide; In tetrahydrofuran; at 0℃; for 1.16667h;
Intermediate 16 (3S)-3-Meth l-1 -[4-(trifluoromethyl)phenyl]sulfonyl}piperazine(2S)-2-Methylpiperazine (15 g, 150 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled down to 0C. Sodium hydroxide (150 mL, 449 mmol) was added, then 4-(trifluoromethyl)benzenesulfonyl chloride (40 g, 164 mmol) (dissolved in 200ml THF) was added dropwise and the resulting mixture was stirred for 1 h. Further 4-(trifluoromethyl)benzenesulfonyl chloride (0.06eq , 2.2g) was added and mixture stirred for 10 min. The mixture was diluted with DCM (500ml) and water (500ml) and stirred for 5 min. The phases were separated, the aqueous layer was extracted with DCM (1000ml) and the organic phases concentrated under reduced pressure. The residue was taken-up with 1 M HCI (500ml) and washed with DCM in order to extracted impurities. The aqueous phase was basified to pH=9 with NaOH 3M, extracted with DCM ( 3x 500ml) and the combined organic phases dried over Na2S04 before the solvent was removed under reduced pressure to give the title compound (30 g).LCMS (low pH) m/z (ES) 309 [M+H]+ 1 H NMR (400 MHz, CDCI3) delta 1 .06 (d, J = 7.2 Hz, 3H), 1.94 (t, J = 10.4 Hz, 1 H), (td, J = 1 1 .2, 4.0 Hz, 1 H), 2.88-3.07 (m, 3H), 3.66 (m, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H) ppm
30 g
With sodium hydroxide; In tetrahydrofuran; water; at 0℃; for 1.16667h;
Intermediate 16 (3S)-3-Methyl-1-[4-(trifluoromethyl)phenyl]sulfonyl}piperazine [0217][0218](2S)-2-Methylpiperazine (15 g, 150 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled down to 0 C. Sodium hydroxide (150 mL, 449 mmol) was added, then 4-(trifluoromethyl)benzenesulfonyl chloride (40 g, 164 mmol) (dissolved in 200 ml THF) was added dropwise and the resulting mixture was stirred for 1 h. Further 4-(trifluoromethyl)benzenesulfonyl chloride (0.06 eq, 2.2 g) was added and mixture stirred for 10 min. The mixture was diluted with DCM (500 ml) and water (500 ml) and stirred for 5 min. The phases were separated, the aqueous layer was extracted with DCM (1000 ml) and the organic phases concentrated under reduced pressure. The residue was taken-up with 1 M HCl (500 ml) and washed with DCM in order to extracted impurities. The aqueous phase was basified to pH=9 with NaOH 3M, extracted with DCM (3×500 ml) and the combined organic phases dried over Na2SO4 before the solvent was removed under reduced pressure to give the title compound (30 g).[0219]LCMS (low pH) m/z (ES) 309 [M+H]+[0220]1H NMR (400 MHz, CDCl3) delta 1.06 (d, J=7.2 Hz, 3H), 1.94 (t, J=10.4 Hz, 1H), (td, J=11.2, 4.0 Hz, 1H), 2.88-3.07 (m, 3H), 3.66 (m, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H) ppm
A dimethyl sulfoxide suspension (5 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (476.1 mg, 1.23 mmol) and (2S)-2-methylpiperazine (616.4 mg, 6.15 mmol) was heated at 100 C. to dissolve and the resulting mixture was stirred at 85 C. for 18.5 hours. (2S)-2-Methylpiperazine (123.3 mg, 1.23 mmol) was added and the resulting mixture was further stirred at 85 C. for 5.5 hours, left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 9:1) to give the title compound (516.0 mg, 93%) as a pale yellow solid.1H-NMR (CDCl3) delta: 0.48-0.57 (4H, m), 1.15 (3H, d, J=6.87 Hz), 1.31-1.41 (1H, m), 2.71 (1H, t, J=11.17 Hz), 2.98-3.15 (4H, m), 3.36-3.45 (2H, m), 3.83-3.89 (4H, m), 3.90-4.02 (2H, m), 4.18-4.41 (4H, brm), 5.60 (2H, brs), 9.24 (2H, s).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 16h;Inert atmosphere;
c) A mixture of (R)-6-bromo-l-(l-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-lH- benzo[i/]imidazole (0.25 g, 0.62 mmol), (5)-(+)-2-methylpiperazine (0.13 g, 1.3 mmol), Pd2(dba)3 (0.028 g, 0.031 mmol), BetaGammaNuAlphaRho (0.057 g, 0.093 mmol), and Cs2C03 (0.60 g, 1.9 mmol) in toluene (10 mL) was purged with nitrogen for 5 min, and then heated at 100 C for 16 h. After cooling to room temperature, the mixture was filtered and washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The resulting crude mixture was diluted with ethyl acetate (20 mL), washed with deionized water and brine, dried ( a2S04), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (Si02, 0-20% methanol in dichloromethane) to afford the coupled product (0.13 g, 0.24 mmol, 39%).
Step D: A mixture of 7-fluoro-3-(4-methylthiazol-2-yl)-2H-chromen-2-one (100 mg, 0.38 mmol), <strong>[74879-18-8](S)-2-methylpiperazine</strong> (46 mg, 0.46 mmol) and DMSO (600 uL) was heated at 80 C for 15 h. The reaction mixture was diluted in an aqueous saturated NaHC03 solution and filtered. The collected material was purified by silica gel column chromatography (10% MeOH in CH2CI2), followed by trituration with 1 : 1 hexane/acetone to yield the title compound (103 mg, 79%) as a yellow solid: m.p. 194-199 C; MS m/z 342.2 [M+H]+; 1H NMR (500 MHz, DMSO- d6): delta 8.80 (1H, s), 7.75 (1H, d, J= 9 Hz), 7.32 (1H, m), 7.06 (1H, dd, J= 9 Hz, 2.5 Hz), 6.91 (1H, d, J= 2.5 Hz), 3.88 (2H, t, J= 11 Hz), 2.96 (1H, d, J= 12 Hz), 2.81 (1H, td, J= 12 Hz, 3 Hz), 2.72 (2H, m), 2.45 (4H, m), 2.36 (1H, br s), 1.04 (3H, d, J= 6.5 Hz).
79%
In dimethyl sulfoxide; at 80℃; for 15h;
Step D: A mixture of 7-fluoro-3-(4-methylthiazol-2-yl)-2H-chromen-2-one (100 mg, 0.38 mmol), <strong>[74879-18-8](S)-2-methylpiperazine</strong> (46 mg, 0.46 mmol) and DMSO (600 muL) was heated at 80 C. for 15 h. The reaction mixture was diluted in an aqueous saturated NaHCO3 solution and filtered. The collected material was purified by silica gel column chromatography (10% MeOH in CH2Cl2), followed by trituration with 1:1 hexane/acetone to yield the title compound (103 mg, 79%) as a yellow solid: m.p. 194-199 C.; MS m/z 342.2 [M+H]+; 1H NMR (500 MHz, DMSO-d6): delta 8.80 (1H, s), 7.75 (1H, d, J=9 Hz), 7.32 (1H, m), 7.06 (1H, dd, J=9 Hz, 2.5 Hz), 6.91 (1H, d, J=2.5 Hz), 3.88 (2H, t, J=11 Hz), 2.96 (1H, d, J=12 Hz), 2.81 (1H, td, J=12 Hz, 3 Hz), 2.72 (2H, m), 2.45 (4H, m), 2.36 (1H, br s), 1.04 (3H, d, J=6.5 Hz).
Step B : A mixture of 7-fluoro-3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one (120 mg, 0.38 mmol), <strong>[74879-18-8](S)-2-methylpiperazine</strong> (75 mg, 0.75 mmol) and DMSO (900 mu,) was heated at 80 C for 15 h. The mixture was diluted with an aqueous saturated NaHC03 solution, causing the product to precipitate from solution. The mixture was filtered. The solid material was purified by silica gel column chromatography (10% MeOH in CH2CI2), yielding the title compound (133 mg, 89%) as a yellow solid: m.p. 250-255 C; MS m/z 393.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6): delta 8.73 (1H, s), 8.52 (1H, d, J = 3 Hz), 8.31 (1H, s), 7.72 (1H, d, J= 8.5 Hz), 7.09 (1H, d, J= 12 Hz), 7.02 (1H, dd, J= 9 Hz, 2 Hz), 6.88 (1H, d, J = 2 Hz), 3.81 (2H, m), 2.96 (1H, m), 2.73 (3H, m), 2.39 (1H, t, J= 11 Hz), 2.31 (1H, br s), 2.28 (3H, s), 1.04 (3H, d, J= 6 Hz).
89%
In dimethyl sulfoxide; at 80℃; for 15h;
Step B: A mixture of 7-fluoro-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one (120 mg, 0.38 mmol), <strong>[74879-18-8](S)-2-methylpiperazine</strong> (75 mg, 0.75 mmol) and DMSO (900 muL) was heated at 80 C. for 15 h. The mixture was diluted with an aqueous saturated NaHCO3 solution, causing the product to precipitate from solution. The mixture was filtered. The solid material was purified by silica gel column chromatography (10% MeOH in CH2Cl2), yielding the title compound (133 mg, 89%) as a yellow solid: m.p. 250-255 C.; MS m/z 393.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6): delta 8.73 (1H, s), 8.52 (1H, d, J=3 Hz), 8.31 (1H, s), 7.72 (1H, d, J=8.5 Hz), 7.09 (1H, d, J=12 Hz), 7.02 (1H, dd, J=9 Hz, 2 Hz), 6.88 (1H, d, J=2 Hz), 3.81 (2H, m), 2.96 (1H, m), 2.73 (3H, m), 2.39 (1H, t, J=11 Hz), 2.31 (1H, br s), 2.28 (3H, s), 1.04 (3H, d, J=6 Hz).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; johnphos; In 1,2-dimethoxyethane; at 80℃; for 4h;Inert atmosphere;
Step B: The alkyne intermediate obtained in Step A (9.33 g, 30.0 mmol) was mixed with <strong>[74879-18-8](S)-2-methylpiperazine</strong> (3.60 g, 36.0 mmol), Pd2dba3 (0.27 g, 0.6 mmol), JohnPhos (0.18 g, 0.6 mmol) and Cs2C03 (13.7 g, 42.0 mmol). The reaction system was purged with argon three times and the solvent DME (60 mL) was added. The suspension was then stirred at 80 C for 4 hours. LC/MS analysis of an aliquot of the reaction mixture revealed a complete consumption of the starting bromide. Solvent was removed on a rotovap and the residue was chromatographed (silica gel, ethyl acetate in dichloromethane 0-50 %) to give (S)-methyl 5-(3-methylpiperazin-l- yl)-2-((trimethylsilyl)ethynyl)benzoate as a brown oil (7.56 g, 79%). MS m/z 331.1 [M+H]+.
Triethylamine (190mul, 1.37mmol) was added to a solution of commercially available <strong>[74879-18-8](S)-(+)-2-methylpiperazine</strong> (125mg, 1.25mmol) in CH2Cl2 (7mL) at 0C and stirred for 5min. p-Toluenesulfonyl chloride (238mg, 1.25mmol) was then added and the mixture was stirred for 1h at 0C before being allowed to warm to room temperature and stirred for a further 4h. Water was then added and the aqueous layer was separated and extracted with CH2Cl2, before being washed sequentially with 1M HCl (50mL), water (50mL), saturated aqueous NaHCO3 solution (50mL) and saturated aqueous sodium chloride solution (50mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to afford tosyl piperazine, (3S)-3-methyl-1-[(4-methylbenzene)sulfonyl]piperazine (310mg, 97%) as a white solid. The product could be used without further purification; mp 138.5-141C (acetone); [alpha]23D=+38.9[alpha]D23=+38.9 (c 0.93, CHCl3); numax (ATR)/cm-1 3352, 2971, 2922, 2863, 2821, 1605, 1452, 1325, 1165, 1133, 1121, 997, 914, 861, 811, 754s, 655; deltaH (500MHz, DMSO-d6) 7.61-7.59 (2H, m, 2×ArH), 7.47-7.44 (2H, m, 2×ArH), 3.41-3.37 (2H, m, CH2NTs), 2.85 (1H, dt, J 12.1 and 2.8, CH2NTs), 2.68-2.60 (2H, m, 3-H and CHHN(H)), 2.41 (3H, s, ArCH3), 2.06 (1H, td, J 11.3 and 3.1, CHHN(H)), 1.70 (1H, t, J 10.8, CHHN(H)), 0.90 (3H, d, J 6.4, 3-(CH3)); deltaC (126MHz, DMSO-d6) 143.4, 131.9, 129.7, 127.5, 52.3, 49.5, 45.9, 44.3, 20.9, 18.8; m/z (CI+) 255 (MH+, 100%), 99 (M+ -Ts, 10); HRMS (CI+) MH+ calculated for C12H19N2O2S 255.1167, observed 255.1164.
(S)-4-((3-methylpiperazin-1-yl)methyl)-N-(4-(trifluoromethyl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.8%
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;
General procedure: To a stirred solution of 39 (5.0 g, 13.5 mmol) in DMF (42 mL) were added triethylamine (3.8 mL) and 1-(pyridin-3-ylmethyl)-piperazine (3.2 g, 18.1 mmol) at room temperature under nitrogen. The stirred mixture was heated at 50C for 3 h. The reaction mixture was cooled to room temperature and diluted with water, THF and EtOAc. The organic extract was washed with water, dried over Na2SO4, filtrated and then concentrated. The crude solid was washed with Et2O/EtOAc and filtrated to afford the title compound 40 as a white solid (6.33 g, 12.4 mmol, 91.5%).
(S)-1-(4-fluorobenzyl)-3-methylpiperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
General procedure: To a stirred mixture of homopiperazine (0.60 g, 6.00 mmol), 4-fluorobenzaldehyde (0.60 g, 5.00 mmol) in DCM (15 mL) wasadded AcOH (0.08 mL, 0.50 mmol) and the mixture was stirred atroom temperature for 0.5 h. Then sodium triacetoxyborohydride(1.60 g, 7.50 mmol) was added in portions. The reaction was stirredat the same temperature for 6 h. Finally, the mixture was dilutedwith saturated aqueous NaHCO3 (15.00 mL) followed by water(15.00 mL) and extracted with EtOAc (3 15.00 mL). The organiclayer was dried (MgSO4), filtered, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (EtOAc/PE 5:1) to afford yellow oil (0.90 g, yield 77%).
7-fluoro-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
[ 74879-18-8 ]
2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
In dimethyl sulfoxide; at 110℃;Sealed tube;
Example 11 2-(2-methylimidazo[l,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]pyrido[l,2- a]pyrimidin-4-one In a sealed tube, 7-fluoro-2-(2-methylimidazo[l,2-b]pyridazin-6-yl)-4H-pyrido[l,2- a]pyrimidin-4-one (Intermediate 1; 50 mg, 0.169 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (68 mg, 0.677 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 110C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2CI2 and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04 and concentrated in vacuo. The crude was purified by column chromatography (S1O2, CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (40 mg, 63%) as a light yellow solid. MS m/z 376.2 [M+H+].
63%
In dimethyl sulfoxide; at 110℃;Sealed tube;
In a sealed tube, 7-fluoro-2-(2-methylimidazo[l,2-b]pyridazin-6-yl)-4H-pyrido[l,2- a]pyrimidin-4-one (Intermediate 1; 50 mg, 0.169 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (68 mg, 0.677 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 110C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2CI2and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04and concentrated in vacuo. The crude was purified by column chromatography (S1O2,CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (40 mg, 63%) as a light yellow solid. MS m/z 376.2 [M+H+].
63%
In dimethyl sulfoxide; at 110℃;Sealed tube;
In a sealed tube, 7-fluoro-2-(2-methylimidazo [1 ,2-b]pyridazin-6-yl)-4H-pyrido [1,2- a]pyrimidin-4-one (Intermediate 1; 50 mg, 0.169 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (68 mg,0.677 mmol, 4.0 eq.) were stuffed in DMSO (2 mL) at 110C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2C12 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2504 and concentrated in vacuo. The crude was purified by column chromatography (5i02, CH2C12/MeOH=95/5 to 90/10) to afford the title product (40 mg, 63%) as a light yellow solid.
63%
In dimethyl sulfoxide; at 110℃;Sealed tube;
In a sealed tube, 7-fluoro-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (Intermediate 1; 50 mg, 0.169 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (68 mg, 0.677 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 110 C. overnight. The solvent was removed under high vacuum. The residue was taken up in CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (SiO2, CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (40 mg, 63%) as a light yellow solid. MS m/z 376.2 [M+H+].
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
[ 74879-18-8 ]
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
In dimethyl sulfoxide; at 120℃;Sealed tube;
Example 8 2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]pyrido[l,2 a]pyrimidin-4-one In a sealed tube, 2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-7-fluoro-pyrido[l,2- a]pyrimidin-4-one (Intermediate 2; 33 mg, 0.107 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (43 mg, 0.427 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 120C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2CI2 and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04 and concentrated in vacuo. The crude was purified by column chromatography (S1O2, CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (18 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H+].
43%
In dimethyl sulfoxide; at 120℃;Sealed tube;
In a sealed tube, 2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-7-fluoro-pyrido[l,2- a]pyrimidin-4-one (Intermediate 2; 33 mg, 0.107 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (43 mg, 0.427 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 120C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2CI2and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04and concentrated in vacuo. The crude was purified by column chromatography (S1O2,CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (18 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H+].
43%
In dimethyl sulfoxide; at 120℃;Sealed tube;
Tn a sealed tube, 2- (2, 8-dimethylimidazo [1 ,2-b]pyridazin-6-yl)-7-fluoro-pyrido [1,2- a]pyrimidin-4-one (Intermediate 2; 33 mg, 0.107 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (43 mg, 0.427 mmol, 4.0 eq.) were stuffed in DMSO (2 mL) at 120C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2C12 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2SO4 andconcentrated in vacuo. The crude was purified by column chromatography (Si02, CH2C12/MeOH=95/5 to 90/10) to afford the title product (18 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H?i.
43%
In dimethyl sulfoxide; at 120℃;Sealed tube;
In a sealed tube, 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-pyrido[1,2-a]pyrimidin-4-one (Intermediate 2; 33 mg, 0.107 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (43 mg, 0.427 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 120 C. overnight. The solvent was removed under high vacuum. The residue was taken up in CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (SiO2, CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (18 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H+].
7-fluoro-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido [1,2-a]pyrimidin-4-one[ No CAS ]
[ 74879-18-8 ]
9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
In dimethyl sulfoxide; at 130℃;Sealed tube;
Example 33 9-methyl-2-(2-methylimidazo[l,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-l- yl]pyrido[l,2-a]pyrimidin-4-one In a sealed tube, 7-fluoro-9-methyl-2-(2-methylimidazo[l,2-b]pyridazin-6-yl)pyrido[l,2- a]pyrimidin-4-one (Intermediate 3; 250 mg, 0.808 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (405 mg, 4.04 mmol, 5.0 eq.) were stirred in DMSO (6 mL) and heated at 130C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2C12 and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04 and concentrated in vacuo. The crude was purified by column chromatography (Si02, CH2Cl2/MeOH=95/5 to 85/15) to afford the title product (135 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H+].
43%
In dimethyl sulfoxide; at 130℃;Sealed tube;
In a sealed tube, 7-fluoro-9-methyl-2-(2-methylimidazo[l,2-b]pyridazin-6-yl)pyrido[l,2- a]pyrimidin-4-one (Intermediate 3; 250 mg, 0.808 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (405 mg, 4.04 mmol, 5.0 eq.) were stirred in DMSO (6 mL) and heated at 130C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2C12and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04and concentrated in vacuo. The crude was purified by column chromatography (Si02,CH2Cl2/MeOH=95/5 to 85/15) to afford the title product (135 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H+].
43%
In dimethyl sulfoxide; at 130℃;Sealed tube;
In a sealed tube, 7-fluoro-9-methyl-2-(2-methylimidazo [1 ,2-b]pyridazin-6-yl)pyrido [1,2- a]pyrimidin-4-one (Intermediate 3; 250 mg, 0.808 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (405 mg,4.04 mmol, 5.0 eq.) were stuffed in DMSO (6 mL) and heated at 130C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2C12 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2504 and concentrated in vacuo. The crude was purified by column chromatography (5i02, CH2C12/MeOH=95/5 to 85/15) to afford the title product (135 mg, 43%) as a light yellow solid.MS m/z 390.3 [M+H?i.
43%
In dimethyl sulfoxide; at 130℃;Sealed tube;
In a sealed tube, 7-fluoro-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (Intermediate 3; 250 mg, 0.808 mmol), and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (405 mg, 4.04 mmol, 5.0 eq.) were stirred in DMSO (6 mL) and heated at 130 C. overnight. The solvent was removed under high vacuum. The residue was taken up in CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (SiO2, CH2Cl2/MeOH=95/5 to 85/15) to afford the title product (135 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H+].
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-9-methyl-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
[ 74879-18-8 ]
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
In dimethyl sulfoxide; at 125℃;Sealed tube;
Example 24 2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-9-methyl-7-[(3S)-3-methylpiperazin-l- yl]pyrido[l,2-a]pyrimidin-4-one In a sealed tube, 2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-7-fluoro-9-methyl- pyrido[l,2-a]pyrimidin-4-one (Intermediate 4; 50 mg, 0.155 mmol) and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (62 mg, 0.619 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 125C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2CI2 and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04 and concentrated in vacuo. The crude was purified by column chromatography (S1O2, CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (45 mg, 72%) as a light yellow solid. MS m/z 404.3 [M+H+].
72%
In dimethyl sulfoxide; at 125℃;Sealed tube;
In a sealed tube, 2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-7-fluoro-9-methyl- pyrido[l,2-a]pyrimidin-4-one (Intermediate 4; 50 mg, 0.155 mmol) and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (62 mg, 0.619 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 125C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2CI2and washed with an aqueous saturated solution of NaHC03. The organic layer was separated and dried over Na2S04and concentrated in vacuo. The crude was purified by column chromatography (S1O2,CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (45 mg, 72%) as a light yellow solid. MS m/z 404.3 [M+H+].
72%
In dimethyl sulfoxide; at 125℃;Sealed tube;
In a sealed tube, 2- (2, 8-dimethylimidazo [1 ,2-b]pyridazin-6-yl)-7-fluoro-9-methyl- pyrido[1,2-a]pyrimidin-4-one (Intermediate 4; 50 mg, 0.155 mmol) and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (62 mg, 0.6 19 mmol, 4.0 eq.) were stuffed in DMSO (2 mL) at 125C overnight. The solvent was removed under high vacuum. The residue was taken up in CH2C12 and washed with an aqueoussaturated solution of NaHCO3. The organic layer was separated and dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (Si02, CH2C12/MeOH=95/5 to 90/10) to afford the title product (45 mg, 72%) as a light yellow solid. MS m/z 404.3 [M+Hi.
72%
In dimethyl sulfoxide; at 125℃;Sealed tube;
In a sealed tube, 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-9-methyl-pyrido[1,2-a]pyrimidin-4-one (Intermediate 4; 50 mg, 0.155 mmol) and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (62 mg, 0.619 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 125 C. overnight. The solvent was removed under high vacuum. The residue was taken up in CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (SiO2, CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (45 mg, 72%) as a light yellow solid. MS m/z 404.3 [M+H+].
7-fluoro-2-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
[ 74879-18-8 ]
7-[(3S)-3-methylpiperazin-1-yl]-2-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With triethylamine; In dimethyl sulfoxide; at 120℃; for 12h;Sealed tube;
In a sealed tube, 7-fluoro-2-(2-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-6-yl)-4H-pyrido[l,2- a]pyrimidin-4-one (Intermediate (VT1), 30 mg, 0.101 mmol), <strong>[74879-18-8](S)-2-methylpiperazine</strong> (30.4 mg, 0.304 mmol, 3 eq.) and TEA (51.2 mg, 70.6 mu, 0.506 mmol, 5 eq.) were dissolved in DMSO (2 ml). The reaction mixture was heated at 120 C for 12 hours. The crude was filtered to afford the title product (29 mg, 77%) as a yellow solid. MS m/z 377.2 [M+H]+.
7-fluoro-2-(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
[ 74879-18-8 ]
7-[(3S)-3-methylpiperazin-1-yl]-2-(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With triethylamine; In dimethyl sulfoxide; at 120℃; for 2.5h;Sealed tube;
In a sealed tube, 7-fluoro-2-(2-methyl-[l,2,4]triazolo[l,5-b]pyridazin-6-yl)-4H-pyrido[l,2- a]pyrimidin-4-one (Intermediate (VI-2), 20 mg, 0.068 mmol), TEA (17.1 mg, 23.5 mu, 0.169 mmol, 5 eq.) and (R)-2-methylpiperazine (20.3 mg, 0.203 mmol, 3 eq.) were combined in DMSO (0.5 ml) and heated at 120C for 2 hours and 30 minutes. The precipitating product was filtered and triturated with diethylether to afford the title product (6 mg, 47%) as a brown solid. MS m/z 377.3 [M+H]+.
Thermometer, vacuum stirrer, four-necked flask 2L equipped with acooling tube, L- tartaric acid 270g (1.8 mol), acetic acid 108 g (1.8 mol), water 270g was added,was completely dissolved. Then, (±) -2- methylpiperazine 300g (3.0 mol), water 300g wasadded, and the reaction was heated 85 C or more, were completely dissolved. Then cooled to6874 C, (R) -2- methylpiperazine and L- diastereomers tartaric was added to precipitatecrystals, allowed to 1 hour aged at that temperature. Then, over a period of 5 hours and cooled to1218 C, and the precipitated crystals were filtered, diastereomeric salt 440g of wet biomass,liquid content 22.7wt%, optical purity of 92.3% e. e. , R KaradaOsamuritsu Retrieving salt to theR-isomer of charge (±) in the 2-methyl piperazine, was 88%. Then, charged 644g of water four-necked flask 2L, the resulting crystals 440g ((R) -2-methylpiperazine pure content = 132 g) were added. Furthermore, the addition of calciumhydroxide 162g (2.2mol), then heated to 80 C, and aged at that temperature for 5 hours.Cooled over a period of 2 hours up to 25 C, was filtered off precipitated crystals to remove thewet material crystal of 586g (mainly L- tartaric acid calcium). Get the filtrate 660 g, liberated with L- tartaric acid in the filtrate (R) -2- methylpiperazine were present 130 g. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, toluene 356g was added to the concentrate, a mixedsolution was heated under normal pressure and azeotroped with water and toluene in arms 84 to87 C, excluding the water. Then, toluene was distilled off 212g under reduced pressure. Theconcentrate was cooled to 47 C, (R) -2- methylpiperazine 0.01g was added as a seed crystal toprecipitate crystals, followed by aging for 1 hour at 47 C. Was cooled over 5 hours 05 C,and aged for 2 hours at 06 C. The precipitated crystals were taken out by filtration underreduced pressure, vacuum drying, the crystalline body (R) -2- methylpiperazine was 45gacquired. The resulting quality of (R) -2- methylpiperazine of the crystal body, chemical purity of100%, an optical purity of 99.5% e. e. In and, R KaradaOsamuritsu acquisition crystals for (R) -2-methylpiperazine in charge filtrate was 69%. 1, illustrating the steps from Reference Example 1 to Example 1. Was the first crystallizationfrom ( "1 crystallization" was described as) (described as "crystallization") last crystallization upto six steps. Compared to the Comparative Example 2 step, short process, was able to get a goodoptically active 2-methylpiperazine of easy nature of handling. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, cyclopentyl methyl ether 356g added to theconcentrated solution, mixed solution was heated to normal pressure and azeotroped water andcyclopentyl methyl ether at 8487 C, except for the water. It was then distilled off cyclopentylmethyl ether 205g under reduced pressure. The concentrate was cooled to 47 C, (R) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals, followed by aging for1 hour at 47 C. Was cooled over 5 hours 05 C, and aged for 2 hours at 06 C. Theprecipitated crystals were taken out by filtration under reduced pressure, vacuum drying, thecrystalline body (R) -2- methylpiperazine was 44g acquired. The resulting quality of (R) -2-methylpiperazine of the crystal body, chemical purity of 100%, an optical purity of 99.6% e. e. Inand, R KaradaOsamuritsu acquisition crystals for (R) -2- methylpiperazine in charge filtrate was 68%. Thermometer, vacuum stirrer, four-necked flask 1L equipped with a Dean-Starkapparatus, 33% (S) -2- methylpiperazine solution 300.0g ((S) -2- methylpiperazine 100.0 g,Quality: Chemistry purity 99.9%, optical purity of 80.0% e.e. ) Were charged. Then stirred withtoluene 586.0g (5.86wt times / (S) -2- methylpiperazine). The solution was heated under normalpressure, arms 84 to 87 was azeotroped with water and toluene in C, except for water only.Then, toluene was distilled off 286g under reduced pressure. The concentrate was cooled to4350 C, (S) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals,followed by aging for 1 hour at 4350 C. Then it cooled over 2 hours to 0 to 5 C, and agedfor 2 hours at 05 C. The precipitated crystals were taken out by filtration under reducedpressure, vacuum drying, the crystalline body (S)-2-methylpiperazine 66.8g was obtained (67%yield). The resulting quality of the crystal of (S) -2- methyl piperazine, the chemical p...
tert-butyl 3-(2-bromophenyl)propyl(methoxymethyl)carbamate[ No CAS ]
[ 74879-18-8 ]
(S)-tert-butyl methoxymethyl(3-(2-(3-methylpiperazin-1-yl)phenyl)propyl) carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 80℃; for 16h;Inert atmosphere;
A solution of tert-butyl-3 -(2-bromophenyl)propyl (methoxymethyl)carbamate (250 mg, 0.70 mmol), ()-2-methylpiperazine (140 mg, 1.40 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), BINAP (87 mg, 0.14 mmol), t-BuONa (202 mg, 2.10 mmol) in PhMe (10 mL) was stirred at 80C for 16 h under N2 atmosphere, then concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 5/1) to afford (S)-tert-butyl-methoxymethyl(3 -(2-(3 -methylpiperazin- 1- yl)phenyl)propyl)carbamate (150 mg, 0.40 mmol, 57%) as a yellow oil. ESI-MS (EI, m/z): 378.0 [M+H].
(S)-7-(3-methylpiperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80 mg
In ethanol; at 80℃; for 8.0h;Microwave irradiation;
A mixture of <strong>[76006-11-6]7-chloro-1H-pyrazolo[3,4-c]pyridine</strong> (200 mg, 1.30 mmol) and (S?)-2- methylpiperazine (1.30g, 13.02 mmol) was dissolved in CH3CH2OH (20 mL). The mixture was stirred at 80 C for 8 h in microwave radiation. The solution was purified by prep-HPLC (Boston C18 21*250mm 1O.im, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford (S)7-(3-methylpiperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine (80 mg, 0.37 mmol) as a white solid. MS (EI+, m/z): 218.2 [M+H]t ?H NIVIR (400 IVIFIz, DMSO-d6) 8.15 (s, 1H), 7.63 (d, J 5.7 Hz, 1H), 7.02 (d, J= 5.7 Hz, 1H), 4.39 (s, 2H), 3.04-2.68 (m, 4H), 2.46 (s, 2H), 1.03 (d, J = 6.3 Hz, 3H).
(S)-1-(4-bromo-3,5-difluoro-2-nitrophenyl)-3-methylpiperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.3%
With N-ethyl-N,N-diisopropylamine; In ethanol; at 85℃; for 16h;
To a stirred solution of 1,3,5-trifluoro-4-nitrobenzene (21 g, 82.38 mmol, 1 eq.) in ethanol (420 mL), was added DIPEA (42.86 mL, 296.09 mmol, 3 eq.) followed by <strong>[74879-18-8](S)-2-methylpiperazine</strong> (9.86 g, 98.43 mmol, 1.2 eq) The resulting reaction mixture was heated at 85 C for 16 h. TLC analysis indicated formation of a polar spot. The reaction mixture was concentrated under reduced pressure and the crude compound was purified by column chromatography (silica gel 100-200) using 5% methanol in DCM as an eluent resulted (S)- 1 -(4-bromo-3,5 -difluoro-2-nitrophenyl)-3- methylpiperazine (21 g, 76.3% yield) as yellow solid. LCMS: [M+Hj 335.97.
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