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[ CAS No. 109-07-9 ] {[proInfo.proName]}

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Product Details of [ 109-07-9 ]

CAS No. :109-07-9 MDL No. :MFCD00005954
Formula : C5H12N2 Boiling Point : -
Linear Structure Formula :- InChI Key :JOMNTHCQHJPVAZ-UHFFFAOYSA-N
M.W : 100.16 Pubchem ID :66057
Synonyms :

Safety of [ 109-07-9 ]

Signal Word:Danger Class:4.1
Precautionary Statements:P210-P240-P241-P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P405-P501 UN#:1325
Hazard Statements:H228-H315-H319-H335 Packing Group:
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Application In Synthesis of [ 109-07-9 ]

* 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.

  • Upstream synthesis route of [ 109-07-9 ]
  • Downstream synthetic route of [ 109-07-9 ]

[ 109-07-9 ] Synthesis Path-Upstream   1~31

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Reference: [1] Patent: US2010/311973, 2010, A1, . Location in patent: Page/Page column 11
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Reference: [1] Patent: US2010/311973, 2010, A1, . Location in patent: Page/Page column 11
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Reference: [1] Patent: US2010/311973, 2010, A1, . Location in patent: Page/Page column 10
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Reference: [1] Patent: US2010/240894, 2010, A1, . Location in patent: Page/Page column 10
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Reference: [1] Patent: US2010/240894, 2010, A1, . Location in patent: Page/Page column 13-15
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Reference: [1] Patent: US2010/240894, 2010, A1, . Location in patent: Page/Page column 12-13; 14
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Reference: [1] Patent: WO2011/130661, 2011, A1,
[2] Patent: WO2017/147700, 2017, A1,
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Reference: [1] Journal of the American Chemical Society, 1951, vol. 73, p. 1838
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Reference: [1] Patent: US2010/240894, 2010, A1, . Location in patent: Page/Page column 13-15
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Reference: [1] Patent: US2010/240894, 2010, A1, . Location in patent: Page/Page column 12
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Reference: [1] Patent: US2010/240894, 2010, A1, . Location in patent: Page/Page column 12-13; 14
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YieldReaction ConditionsOperation in experiment
68%
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
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Reference: [1] Patent: JP2016/37495, 2016, A,
[2] Patent: WO2004/829, 2003, A1,
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YieldReaction ConditionsOperation in experiment
68%
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
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YieldReaction ConditionsOperation 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.
Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 22-23
[2] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 21-22
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  • [ 94695-52-0 ]
  • [ 109-07-9 ]
  • [ 103460-89-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 3, p. 1142 - 1154
  • 17
  • [ 109-07-9 ]
  • [ 501-53-1 ]
  • [ 84477-85-0 ]
YieldReaction ConditionsOperation in experiment
85.1% at 0 - 8℃; for 2 h; Example 1
In a 100 ml four-neck flask, 5.00 g (= 0.0499 mole) of racemic 2-methylpiperazine was placed, and 44 g of 1-butanol (water content 0.05 wtpercent) was added for dissolution.
The solution was cooled to 0°C, and 8.47 g of benzyl chlorocarbonate (= 0.0489 mole, purity by HPLC determination analysis 98.5 wtpercent, 0.98 molar time) was added dropwise in a liquid temperature range from 0 to 8°C.
Then, stirring was carried out at 0 to 5°C for 2 hours, and the reaction solution was partially sampled and determined by the internal standard method (internal standard: anisole).
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 83.9percent (based on the amount of 2-methylpiperazine).
The reaction solution was further stirred at room temperature for 12 hours and analyzed.
As a result, the reaction yield was 85.1percent.
Example 3 A reaction was performed as described for Example 1, except that the amount of benzyl chlorocarbonate used was changed from 8.47 g to 10.1 g (= 0.0597 mole, 1.17 molar times). As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 93.8percent (based on the amount of 2-methylpiperazine) after lapse of 2 hours at 0 to 5°C. Stirring was carried out at room temperature for further 12 hours, being followed by analysis. As a result, the reaction yield was 95.1percent.
83.4% at 0℃; for 2 h; Example 6
A reaction was carried out as described for Example 1, except that the solvent was changed from 44 g of 1-butanol to 44 g of ethanol (water content 0.06 wtpercent).
After stirring at 0°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 83.4percent (based on the amount of 2-methylpiperazine).
82.5% With pyridine In water; butan-1-ol at 0 - 10℃; for 2 h; Example 8
In a 100 ml four-neck flask, 5.04 g (= 0.0503 mole) of racemic 2-methylpiperazine was placed, and 5.37 g of water and 45.13 g of 1-butanol were added for dissolution (water content 10.6 wtpercent).
Furthermore, 3.99 g (= 0.0504 mole) of pyridine was added, being followed by stirring and subsequent cooling down to 0°C, and 8.67 g of benzyl chlorocarbonate (= 0.0494 mole, purity by HPLC determination analysis 97.1 wtpercent, 0.98 molar time) was added dropwise with the liquid temperature kept in a range from 5 to 10°C.
Then, stirring was carried out at 0°C for 2 hours.
The reaction solution was analyzed, and as a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 82.5percent.
47% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3 h; Step 1: CbzCl (17 g, 0.1 mol) was added into a solution of compound 219-1 (30 g, 0.3 mol) and DIPEA (40 g, 0.3 mol) in DCM (200 mL) at 0°C, then the mixture was stirred at room temperature for 3h and the solvent was removed, the crude product was purified by column chromatography to deliver compound 2 (11 g, yield 47percent) as yellow oil. MS ESI calcd for C13H18N2O2 [M+H]+ 235, found 235.
37.7% at 0℃; for 2 h; Comparative example 6 A reaction was carried out as described for Example 6, except that the solvent was changed from 44 g of ethanol to a mixed solvent consisting of 22 g of water and 22 g of ethanol (water content 50.0 wtpercent). As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 37.7percent (based on the amount of 2-methylpiperazine).
33.6% at 0 - 5℃; for 2 h; Example 5
A reaction was carried out as described for Example 1, except that the solvent was changed from 44.7 g of 1-butanol to a mixed solvent consisting of 5.3 g of water and 40 g of 1-butanol (water content 10.6 wtpercent).
After stirring at 0 to 5°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 82.1percent (based on the amount of 2-methylpiperazine).
Comparative Example 1
A reaction was carried out as described for Example 1, except that the solvent was changed from 44 g of 1-butanol to a mixed solvent consisting of 9 g of water and 35 g of 1-butanol (water content 20.5 wtpercent).
After stirring at 0 to 5°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 59.6percent (based on the amount of 2-methylpiperazine).
Comparative Example 2
A reaction was carried out as described for Example 4, except that the solvent was changed from 44 g of 1-butanol to a mixed solvent consisting of 18 g of water and 27 g of 1-butanol (water content 40.0 wtpercent).
After stirring at 0°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 51.6percent (based on the amount of 2-methylpiperazine).
Comparative Example 3
A reaction was carried out as described for Example 1, except that the solvent was changed from 44 g of 1-butanol to a mixed solvent consisting of 22 g of water and 22 g of 1-butanol (water content 50 wtpercent).
After stirring at 0°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 33.6percent (based on the amount of 2-methylpiperazine).

Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 16; 17
[2] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 18
[3] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 19
[4] Synthetic Communications, 2007, vol. 37, # 20, p. 3623 - 3634
[5] Patent: EP3124482, 2017, A1, . Location in patent: Paragraph 0476; 0477
[6] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 18
[7] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 17; 18
[8] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 3, p. 770 - 773
[9] Patent: EP1122242, 2001, A1,
[10] Patent: US6673799, 2004, B1, . Location in patent: Page column 14
  • 18
  • [ 109-07-9 ]
  • [ 501-53-1 ]
  • [ 84477-85-0 ]
  • [ 29906-54-5 ]
  • [ 100-51-6 ]
YieldReaction ConditionsOperation in experiment
94.5%
Stage #1: at 0 - 20℃; for 14 h;
Stage #2: With sodium hydroxide In water; toluene
Example 2
A reaction was performed as described for Example 1, except that the amount of benzyl chlorocarbonate used was changed from 8.45 g to 9.25 g (= 0.0533 mole, 1.07 molar times).
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 91.7percent (based on the amount of 2-methylpiperazine) after lapse of 2 hours at 0 to 5°C.
Furthermore, the reaction solution was stirred at room temperature for further 12 hours and analyzed.
As a result, the reaction yield was 94.5percent.
From the obtained reaction solution, 1-butanol was distilled away, and 30 g of water was added to the concentrate.
The pH was adjusted to 11.2 using 48percent sodium hydroxide.
To the solution, 40 g of toluene was added, and the lower layer was removed.
Subsequently, the upper layer was concentrated under reduced pressure to distill away toluene, for obtaining 11.1 g of a recovered solution.
The obtained recovered solution was analyzed, and as a result, the intended 1-bunzyloxycarbonyl-3-methylpiperazine occupied 87.2 area percent, and as for impurities, benzyl alcohol occupied 0.52 area percent, 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.01 area percent, 1-benzyl-2-methylpiperazine, 0.10 area percent, and 1,4-dibenzyloxycarbonyl-2-methylpiperazine, 11.9 area percent (solvent toluene, 1.9 area percent).
Therefore, the total of impurities was 6 liquid chromatography area percent.
Example 12 The reaction solution obtained by the same operation as in Example 2 was concentrated and 31 g of 1-butanol was distilled away under reduced pressure, being followed by addition of 30 g of water. Subsequently 35percent hydrochloric acid water was used for adjusting the pH to 0.8. Then, 22 g of toluene was added, and stirring was carried out for 30 minutes. The upper layer was then removed, and the same amount of toluene was added again. The same operation was repeated for carrying out washing operation. Subsequently 48percent sodium hydroxide aqueous solution was used to keep the pH of the reaction solution at 11.5. In this case, white turbidity occurred due to 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 70°C in temperature. Then, toluene was distilled away to obtain 10.13 g of 1-benzyloxycarbonyl-3-methylpiperazine. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 98.0 liquid chromatography area percent. The impurities showed 0.40 liquid chromatography area percent for benzyl alcohol, 0.04 liquid chromatography area percent for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.10 liquid chromatography area percent for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (1.46 liquid chromatography area percent for solvent toluene). Therefore, the total of impurities was 0.55 liquid chromatography area percent.Example 13 The reaction solution obtained by the same operation as in Example 2 was concentrated and 28 g of 1-butanol was distilled away under reduced pressure, being followed by addition of 30 g of water. Subsequently 35percent hydrochloric acid water was used for adjusting the pH to 0.7. Then, 22 g of toluene was added, and stirring was carried out for 30 minutes. The upper layer was then removed, and the same amount of toluene was added again. The same operation was repeated for carrying out washing operation. Subsequently 48percent sodium hydroxide aqueous solution was used to keep the pH of the reaction solution at 11.8. In this case, white turbidity occurred due to 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 70°C in temperature. Then, toluene was distilled away. Ten point three two grams of the obtained 1-benzyloxycarbonyl-3-methylpiperazine was placed in a 10 ml heart flask and distilled in vacuum. When the oil bath reached 145°C, the removal by distillation started, and the temperature was raised finally up to 170°C. The internal pressure ranged from 40 to 53 Pa, and the temperature at the column top ranged from 131 to 140°C. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 99.7 liquid chromatography area percent. The impurities showed 0.03 liquid chromatography area percent for benzyl alcohol, 0.18 liquid chromatography area percent for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.04 liquid chromatography area percent for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (for solvent toluene either). Therefore, the total of impurities was 0.25 liquid chromatography area percent.
Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 16; 20-21
  • 19
  • [ 109-07-9 ]
  • [ 215657-34-4 ]
  • [ 84477-85-0 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 18, p. 2973 - 2974
[2] Tetrahedron, 2000, vol. 56, # 32, p. 5843 - 5856
  • 20
  • [ 109-07-9 ]
  • [ 300561-17-5 ]
  • [ 84477-85-0 ]
Reference: [1] Tetrahedron, 2000, vol. 56, # 32, p. 5843 - 5856
  • 21
  • [ 109-07-9 ]
  • [ 105784-61-0 ]
Reference: [1] Canadian Journal of Chemistry, 1992, vol. 70, # 5, p. 1323 - 1327
  • 22
  • [ 24424-99-5 ]
  • [ 109-07-9 ]
  • [ 120737-59-9 ]
YieldReaction ConditionsOperation in experiment
96.5% at 20℃; for 24 h; 1)
3-Methylpiperazine-1-carboxylic acid tert-butyl ester
Di-tert-butyl dicarbonate (21.7 g) was added at room temperature to 2-methylpiperazine (10.0 g) in methanol (200 mL), followed by stirring for 24 hours.
The reaction solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform - methanol), to thereby give 3-methylpiperazine-1-carboxylic acid tert-butyl ester as an oily product (19.3 g, 96.5percent).
1H-NMR (300MHz, CDCl3) δ: 1.04 (3H, d, J=6.24Hz), 1.46(9H,s), 2.39(1H,br s), 2.70-2.77(3H,m), 2.94(1H,br s), 3.93(2H,br s).
MS(FAB)m/z:201(M+H)+.
83% With triethylamine In dichloromethane at 0 - 20℃; for 16 h; Inert atmosphere To a stirring solution of 2-methylpiperazine 7 (3 g, 30.00 mmol) in CH2C12 (100 mL) under argon atmosphere were added triethylamine (9 mL, 90.00 mmol) and Boc-anhydride (7.2 mL, 33.00 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with -pentane (2 x 20 mL) and dried in vacuo to afford compound 9 (5 g, 83percent) as off- white solid. TLC: 5percent MeOH/ CH2C12 (R/. 0.4); 1H-NMR (OMSO-d6, 400 MHz): δ 3.80- 3.62 (m, 2H), 3.27-3.09 (m, 2H), 2.83-2.71 (m, 2H), 2.37-2.17 (m, 1H), 1.39 (s, 9H), 0.92 (d, J= 6.3 Hz, 3H).
81.5% at 0 - 15℃; for 2 h; Example 9 In a 100 ml four-neck flask, 5.06 g (= 0.0505 mole) of racemic 2-methylpiperazine was placed, and 50.00 g of 1-butanol (water content 0.05 wtpercent) was added for dissolution. After cooling down to 0°C, 10.91 g (= 0.0500 mole, 0.99 molar time) of di-tert-butyl dicarbonate was added dropwise with the liquid temperature kept in a range from 5 to 15°C. Then, stirring was carried out at 5 to 10°C for 2 hours. The reaction solution was analyzed, and as a result, the conversion of 2-methylpiperazine was 94.7percent, while the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 89.3percent (reaction yield 84.6percent).Example 10 An experiment was carried out as described for Example 9, except that the amount of di-tert-butyl dicarbonate used was changed to 11.97 g (= 0.0548 mole, 1.10 molar times). As a result, the conversion of 2-methylpiperazine was 100.0percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 81.5percent (reaction yield 81.5percent).
75% With pyridine In dichloromethane at 0 - 20℃; General Procedure 1. Chemoselective N-acylation reaction of 2-substitued piperazines (6-9, 43-45). 2-Substituted piperazine (6.0 mmol) was dissolved in dry dichloromethane (80 mL) and cooled to 0 oC. A solution of the appropriate acylating agent in dichloromethane (6.0 mmol, 20 mL) was added dropwise in 30 minutes, and then pyridine (9 mmol). The reaction mixture was kept into an ice-water bath with stirring 12 hours and left at room temperature until TLC showed that all the starting material had reacted. The reaction mixture was evaporated to dryness to obtain the corresponding monoacylderivative. Column chromatography gave the pure compounds in high yields. l-tert-Butoxycarbonyl-3-methylpiperazine (6).37 The product was obtained as a syrup and purified by column chromatography using dichloromethane-methanol (15:1) as eluent (0.90 g, 75percent yield). MS (CI): m/z 201 (20percent) [M+H]+. 1H NMR (500 MHz, DMSO-d6) 0 3.75-3.7 1 (m, 2H), 2.85-2.82 (m, 1H), 2.75-2.69 (m, 1H), 2.60-2.54 (m, 3H), 2.39-2.34 (m, 1H), 1.41 (s, 9H), 0.96 (d, J = 6.3 Hz, 3H). 13C RMN (125 MHz, DMSO-d6) δ 154.5, 79.3, 51.2, 50.5, 45.5, 44.4, 28.6, 19,3. HRMS (m/z): calcd. for C10H20N2O2 200.1528 [M]+.; found 200.1525.
65.9%
Stage #1: at 0 - 15℃; for 2 h;
Stage #2: With sodium hydroxide In water at 0 - 26℃; for 2.5 h;
Comparative Example 10 A 200 ml four-neck flask with a pH meter and dropping funnel was charged with 10.08 g (= 0.101 mole) of racemic 2-methylpiperazine, and 50.0 g of 1-butanol was added for dissolution, being followed by addition of 50.3 g of water (water content 50.1 wtpercent). With vigorous stirring, benzyl chlorocarbonate was added dropwise. In this case, 48 wtpercent sodium hydroxide aqueous solution was added dropwise to keep the pH value of the system at 10 to 11, and as required, the system was cooled with ice to keep the internal temperature at 23 to 26°C (final water content 53.2 wtpercent). After completion of dropwise addition, with vigorous stirring, aging was carried out for 2.5 hours. The reaction solution was sampled and analyzed, and as a result, the conversion of 2-methylpiperazine was 85.5percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 77.2percent (reaction yield 66.0percent).Comparative Example 11 A 200 ml four-neck flask with a pH meter and dropping funnel was charged with 10.22 g (= 0.102 mole) of racemic 2-methylpiperazine, and 80.5 g of 1-butanol was added for dissolution, being followed by addition of 27.5 g of water (water content 25.4 wtpercent). With vigorous stirring, benzyl chlorocarbonate was added dropwise. In this case, 48 wtpercent sodium hydroxide aqueous solution was added dropwise to keep the pH value of the system at 8 to 9.5, and as required, the system was cooled with ice to keep the internal temperature at 23 to 26 (final water content 26.9 wtpercent). After completion of dropwise addition, with vigorous stirring, aging was carried out for 2.5 hours. The reaction solution was sampled and analyzed, and as a result, the conversion of 2-methylpiperazine was 89.6percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 73.5percent (reaction yield 65.9percent).
42% With triethylamine In dichloromethane at 0 - 20℃; To a solution of 2-methyl-piperazine (2.0 g, 0.02 mol) and triethylamine (6 mL) in methylene chloride (15 mL) at 0° C. was added (Boc)2O (4.14 g, 0.019 mol) dropwise. The mixture was stirred at room temperature for 1 hour, and then the solvent was removed by rotary evaporation. The residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate and brine, dried over Na2SO4, and purified by column chromatography on silica gel (DCM:MeOH:Et3N=75:1:0.2) to give an white solid (1.65 g, 42percent). LC-MS (ESI) m/z: 201 (M+1)+.
42% With triethylamine In dichloromethane at 0 - 20℃; for 1 h; Example 126Atert-Butyl 3-methylpiperazine- 1 -carboxylate[00770] To a solution of 2-methyl-piperazine (2.0 g, 0.02 mol) and triethylamine (6 mL) in methylene chloride (15 mL) at 0 °C was added (Boc O (4.14 g, 0.019 mol) dropwise. The mixture was stirred at room temperature for 1 hour, and then the solvent was removed by rotary evaporation. The residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate and brine, dried over Na2S04, and purified by column chromatography on silica gel (DCM: MeOH:Et3N = 75 : 1 : 0.2) to give an white solid (1.65 g, 42percent). LC-MS (ESI) m/z: 201 (M+l)+.
33.9% at 0 - 15℃; for 2 h; Example 11 An experiment was carried out as described for Example 9, except that 45.55 g of 1-butanol and 4.61 g of water (water content 9.2 wtpercent) were used instead of 50.00 g of 1-butanol. As a result, the conversion of 2-methylpiperazine was 94.3percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 85.8percent (reaction yield 80.9percent).Comparative Example 8 An experiment was carried out as described for Example 9, except that 37.56 g of 1-butanol and 12.67 g of water (water content 25.2 wtpercent) were used instead of 50.00 g of 1-butanol. As a result, the conversion of 2-methylpiperazine was 81.6percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 70.9percent (reaction yield 57.9percent).Comparative Example 9 An experiment was carried out as described for Example 9, except that 25.00 g of 1-butanol and 25.00 g of water (water content 50.0 wtpercent) were used instead of 50.00 g of 1-butanol. As a result, the conversion of 2-methylpiperazine was 81.2percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 41.8percent (reaction yield 33.9percent).

Reference: [1] Patent: US2003/153556, 2003, A1,
[2] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 33
[3] Patent: WO2016/168619, 2016, A1, . Location in patent: Paragraph 00286
[4] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 19
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5432 - 5448
[6] Patent: WO2017/144624, 2017, A1, . Location in patent: Page/Page column 21
[7] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 20
[8] Patent: US5300506, 1994, A,
[9] Patent: US2009/281114, 2009, A1,
[10] Patent: US5434154, 1995, A,
[11] Patent: US2010/35883, 2010, A1, . Location in patent: Page/Page column 92
[12] Patent: WO2011/130661, 2011, A1, . Location in patent: Page/Page column 180
[13] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 19
[14] Patent: US6825200, 2004, B1, . Location in patent: Page column 28
[15] Patent: US6673799, 2004, B1, . Location in patent: Page column 12
[16] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 23, p. 4947 - 4957
[17] Patent: WO2017/147700, 2017, A1, . Location in patent: Paragraph 00481
  • 23
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  • [ 91612-43-0 ]
  • [ 120737-59-9 ]
YieldReaction ConditionsOperation in experiment
89% at 0℃; for 2 h; [Referential Example 82]; 3-Methylpiperazine-1-carboxylic acid tert-butyl ester; [] 2-Methylpiperazine (3.19 g) was added to 2-(tert-butylcarbonyloxyimino)-2-phenylacetonitrile (7.87 g) in tetrahydrofuran (100 mL) at 0°C, followed by stirring for 2 hours. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was purified through silica gel column chromatography (chloroform - 7N ammonia/methanol mixture), to thereby give the title compound as an oily product (5.70 g, 89percent).1H-NMR(400MHz,CDCl3)δ: 1.05(3H,d,J=6.4Hz), 1.46(9H,s), 2.40(1H,br), 2.65-2.84(3H,m), 2.90-3.00(1H,br), 3.94(2H,br). MS(ESI)m/z: 201(M+H)+.
Reference: [1] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 61
  • 24
  • [ 109-07-9 ]
  • [ 73371-96-7 ]
  • [ 120737-59-9 ]
YieldReaction ConditionsOperation in experiment
89% at 0℃; for 2 h; 2-Methylpiperazine (3.19 g) was added at 0°C to 2-(tert-butylcarbonyloxyimino)-2-phenylacetonitrile (7.87 g) in tetrahydrofuran (100 mL), and the mixture was stirred for 2 hours. The reaction solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform - 7N ammonia/methanol), to thereby give the title compound as an oil (5.70 g, 89percent). 1H-NMR(400MHz,CDCl3)δ:1.05(3H,d,J=6.4Hz), 1.46(9H,s), 2.40 (1H,br), 2.65-2.84(3H,m), 2.90-3.00 (1H,br), 3.94(2H,br). MS(ESI)m/z:201(M+H)+.
Reference: [1] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 39-40
  • 25
  • [ 58632-95-4 ]
  • [ 109-07-9 ]
  • [ 120737-59-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 6, p. 690 - 698
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  • [ 109-07-9 ]
  • [ 120737-59-9 ]
Reference: [1] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 339
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  • [ 109-07-9 ]
  • [ 120737-59-9 ]
Reference: [1] Patent: US4880808, 1989, A,
  • 28
  • [ 109-07-9 ]
  • [ 120737-59-9 ]
Reference: [1] Patent: EP1122242, 2001, A1,
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  • [ 55130-19-3 ]
  • [ 120737-59-9 ]
Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 1, p. 209 - 215
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  • [ 120737-78-2 ]
Reference: [1] Patent: WO2011/130661, 2011, A1,
[2] Patent: JP6378918, 2018, B2,
[3] Patent: WO2007/135427, 2007, A1,
  • 31
  • [ 109-07-9 ]
  • [ 501-53-1 ]
  • [ 444666-46-0 ]
YieldReaction ConditionsOperation in experiment
50.4% With sodium hydroxide In water; butan-1-ol at 23 - 26℃; for 2 h; Comparative Example 5
A 200 ml four-neck flask with a pH meter and dropping funnel was charged with 10.02 g (= 0.100 mole) of racemic 2-methylpiperazine, and 80.2 g of 1-butanol was added for dissolution, being followed by addition of 20.1 g of water (water content 20.0 wtpercent).
With vigorous stirring, benzyl chlorocarbonate was added dropwise.
In this case, 48 wtpercent sodium hydroxide aqueous solution was added dropwise to keep the pH value of the system at 7.5 to 8.5, and as required, the system was cooled with ice to keep the internal temperature at 23 to 26 (final water content 23.0 wtpercent).
After completion of dropwise addition, with vigorous stirring, aging was carried out for 2 hours.
The reaction solution was sampled and analyzed, and as a result, the reaction yield of 1-benzyloxycarbonyl-2-methylpiperazine was 50.4percent.
40.1% With sodium hydroxide In water; butan-1-ol at 23 - 26℃; for 2 h; Comparative Example 4
A 200 ml four-neck flask with a pH meter and dropping funnel was charged with 10.02 g (= 0.100 mole) of racemic 2-methylpiperazine, and 50.0 g of 1-butanol was added for dissolution, being followed by addition of 50.1 g of water (water content 50.0 wtpercent).
With vigorous stirring, benzyl chlorocarbonate was added dropwise.
In this case, 48 wtpercent sodium hydroxide aqueous solution was added dropwise to keep the pH value of the system at 10 to 11, and as required, the system was cooled with ice to keep the internal temperature at 23 to 26°C (final water content 52.1 wtpercent).
After completion of dropwise addition, with vigorous stirring, aging was carried out for 2 hours.
The reaction solution was sampled and analyzed, and as a result, the reaction yield of 1-benzyloxycarbonyl-2-methylpiperazine was 40.1percent.
Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 18
[2] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 18
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Chemical Structure| 1152367-80-0

[ 1152367-80-0 ]

(S)-1,3-Dimethylpiperazine

Similarity: 0.89

Chemical Structure| 84477-72-5

[ 84477-72-5 ]

2,2-Dimethylpiperazine

Similarity: 0.85