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Structure of 75336-86-6 * 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.
With sodium hydroxide In branched octane; water at 80℃; for 2 h;
(R)-2-methylpiperazine, L-tartrate from Example 4 in H20 (182 L), and Branched octanes (200 L) were added to a 4000 L reactor and stirred until dissolved. More branched octanes (530 L) were added to the 4000 L reactor followed by 50percent [NAOH] (1120 kg) at a temperature between [35°C] and [52°C.] The solution was heated to [80°C] and stirred [FOR 2H.] The solution was settled and the lower aqueous phase was transferred to the 4000 L receiver. The solution in the 4000 L reactor was cooled [TO-21°C] and filtered onto a 48"Nutsche filter sending the filtrate to a 1200 L reactor. The 4000 L reactor and 48"Nutsche filter were rinsed with branched octanes (300 L). The solids were dried with [25°C] nitrogen and collected to yield 24.9 kg (67percent) of the title compound [OF NLT] 99percent ee as determined by chiral HPLC assay. The aqueous solution in the 4000 L receiver was adjusted to pH 8.4 with acetic acid (812 kg) before disposal. The yield of the title compound according to D2, starting from (R)-2-methyl- piperazine, L-tartrate was 42percent. M. Pt. [91-93°C.] 'H NMR (400 MHz, [CDC13)] : [No. ] 2.97-2. 68 (6H, [M),] 2. [35] [(1H,] dd, J = 11.7, 10.2 Hz), 1.61 (2H, s), 1.00 (3H, d, J = 6.7 Hz), 0.00 (TMS, reference). [APOS;3C] NMR (100 MHz, CDC13) : [6] 54.14 (t), [51.] 89 (d), 47.43 (t), 46.46 (t), 20.08 (q), 0.00 (TMS, reference). IR (mull) 3220 (s, b), 2819 (s), 2748,2042 (w), 1995 (w), 1981 (w), 1328, 1279,1137, 1094,960, 859 (s), 845 (s), 795 (s), 621 (s), [CMAPOS;APOS;.] HRMS (FAB) calcd for [C5HZ2N2] [+HI] 101.1079, found 101.1080. [[A,] 25D = _17°] (c 0.85, [CH2CI2).] Anal. Calcd for [C5HI2N2] : C, 59.96 ; H, 12.07 ; N, 27.97. Found: C, 59.25 ; H, 11.71 ; N, 27. [64.]
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
3
[ 13264-88-5 ]
[ 75336-86-6 ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium methylate In methanol at 25℃; for 1 h;
Purified diastereomeric salt 41.3g (69mmol), dichloromethane 140ml, 35percent hydrochloric acid 25.0g (0.24mol), a mixture of distilled water 25ml to Kaishio, solid content was allowed to standfor liquid separation Upon dissolution. The resulting aqueous layer was concentrated to drynessto give (R) -2- methylpiperazine dihydrochloride 11.7 g. [Α] D: + 5.33 ° (C = 1.0 formic acid) (R)-2- methyl piperazine dihydrochloride 10.0g (58mmol) and 28percent sodium methoxide methanolsolution 23.2g the (0.12mol) was stirred for 1 hour free at 25 ° C. After filtering off theinsoluble matter, the solvent was evaporated. Residue to heating by the addition of cyclohexane30ml, after reflux, and the insoluble matter was filtered hot, and cooled to 20 ° C. The resultingcrystals isolated and dried to give (R)-2-methylpiperazine 4.5 g (60.0percent yield). [Α] D: -20.3 ° (C =1.0 t- butyl methyl ether), an optical purity of 99.6percent e. e. , Was a melting point of 90 ° C.
Reference：
[1] Patent: JP2016/37495, 2016, A, . Location in patent: Paragraph 0064
Reference：
[1] Chemistry Letters, 1988, p. 513 - 516
17
[ 109-07-9 ]
[ 75336-86-6 ]
[ 74879-18-8 ]
Yield
Reaction Conditions
Operation 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
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 1, p. 254 - 260
20
[ 24424-99-5 ]
[ 75336-86-6 ]
[ 163765-44-4 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 0 - 20℃; for 4 h;
To a solution of (R)-methylpiperazine (400 mg) in dichloromethane (20 mL) at 0 0C was added di-tert-butyl dicarbonate (871 mg). The reaction was stirred at room <n="194"/>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 (R)-3-methyl-piperazine-l- carboxylic acid tert-butyl ester as a white solid (669 mg, 84percent).
50%
at 0 - 20℃;
(R)-2-methylpiperazine (5.025 g, 50.2 mmol) was dissolved in DCM (100 mL). A solution of boc anhydride (5.47 g, 25.1 mmol) in DCM (50 mL) was added dropwise at 0° C. The reaction mixture was stirred at rt for 1 h. The solution was filtered and concentrated under reduced pressure. Water (100 mL) was added to the residue, which 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 5.04 g title compound (50percent) as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.03 (d, J=6.3 Hz, 3H) 1.45 (s, 9H) 1.56 (s, 1H) 2.30-2.46 (m, 1H) 2.65-2.72 (m, 1H) 2.74-2.76 (m, 2H) 2.93-2.95 (m, 1H) 3.93 (br s, 2H).
50%
at 0 - 20℃;
(R)-2-methylpiperazine (5.025 g, 50.2 mmol) was dissolved in DCM (100 mL). A solution of boc anhydride (5.47 g, 25.1 mmol) in DCM (50 mL) was added dropwise at 0° C. The reaction mixture was stirred at rt for 1 h. The solution was filtered and concentrated under reduced pressure. H2O (100 mL) was added to the residue, which 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 5.04 g Intermediate D (50percent) as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.03 (d, J=6.3 Hz, 3H) 1.45 (s, 9H) 1.56 (s, 1H) 2.30-2.46 (m, 1H) 2.65-2.72 (m, 1H) 2.74-2.76 (m, 2H) 2.93-2.95 (m, 1H) 3.93 (br s, 2H). Intermediate D is also commercially available from Lanzhou Boc Chemical Co.
With potassium carbonate In acetonitrile at 20 - 60℃; for 2 h;
To a mixture of 6-chloropyridine-3-carbonitrile (10 g, 0.06 mol) and (2R)-2-methylpiperazine(6.35 g, 0.06 mol) in acetonitrile (80 mL), K2C03 (12.0 g, 0.09 mol) was added at RT. Theresulting mixture was stirred at 60°C for 2 h (TLC indicated complete consumption ofstarting material). The reaction was brought toRT, quenched with water (150 mL) andextracted with EtOAc (3 x 80 mL). The combined organic extracts were dried over anhydrousNa2S04 and concentrated under reduced pressure. The residue was purified by columnchromatography (100-200 silica gel, 5percent MeOH-DCM) to afford 6-[(3R)-3-methylpiperazine-1-yl]-pyridine-3-carbonitrile (10.0 g, 69percent yield).
59%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 36 h;
Triethylamine (5.51 g, 4 mL, 54.6 mmol, 2.7 eq) is added to a solution of 6-chloro- nicotinonitrile (2.76 g, 20 mmol, 1 eq), (i?)-2-methyl- piperazine (2.0Og, 20 mmol, 1 eq) in DMF (15 mL), and the resulting solution is stirred at rt for 36 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 (2.3 g, 59percent). IH NMR (400 MHz, CHLOROFORM-*/) δ ppm 8.32 (d, J=2.40 Hz, 1 H), 7.52 (dd, J=9.09, 2.27 Hz, 1 H), 6.52 (d, J=8.97 Hz, 1 H), 4.14 - 4.24 (m, 2 H), 3.01 - 3.07 (m, 1 H), 2.72 - 2.94 (m, 3 H), 2.52 (dd, J=12.76, 10.36 Hz, 1 H), 1.07 (d, J=6.32 Hz, 3 H).
Reference：
[1] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 80
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3954 - 3968
[3] Patent: WO2008/110611, 2008, A1, . Location in patent: Page/Page column 34
With triethylamine; In dichloromethane; acetonitrile; at 20 - 30℃; for 1.5h;
To the 1200 L reactor was dissolved (R)-2-methylpiperazine from Example 5 (25 kg) in CH3CN (319 kg) at [15°C] to [25°C] until dissolution was complete (10 min. ) After cooling to [5°C] to [10°C] Et3N (63 kg) was added. To the 1200 L receiver trityl chloride (69.5 kg) was dissolved in CH2C12 (106 kg) at [15°C] to [25°C.] The solution in the receiver was transferred to the reactor over 0.5 h with a CH2C12 rinse (27 kg), and the solution was heated to [20°C] to [30°C.] The reaction was monitored by GLC and was complete in 1 h. The resulting slurry was cooled to [8°C] to [12°C,] filtered onto a 48"Nutsche filter, and rinsed with CH3CN (40 kg at [8°C] to [12°C).] The filter cake was dried using [50°C] to [55°C] nitrogen to afford 25.26 kg of the by-product [ET3NHCL] (74percent yield; easy to filter off the by-product). The filtrate was transferred to the 1200 L reactor and cooled further [TO-8°C] [TO-10°C] for 1 h. The resulting slurry was filtered onto a 24"Nutsche filter and rinsed [WITH-8°C] to-10°C CH3CN (24 kg) sending the filtrate and rinse to the 1200 L receiver. The filter cake was dried with [50°C] to [55°C] nitrogen to afford another 2.98 kg [ET3NHCL] (9percent yield). The filtrate was transferred to the 1200 L reactor with a CH3CN (10 kg) rinse, and distilled under vacuum to an oil of the title compound of 97.99percent GC purity. The yield was quantitative. M. Pt. [134-136°C.] [APOS;H] NMR (400 MHz, CDC13) : [6] 7.55-7. 40 (6H, br s), 7.25 (6H, t, J = 7. 9 Hz), 7.14 (3H, t, [J =] 7.1 Hz), 3.21-3. 13 (2H, [M),] 3. [10-2. 90 (1H,] br s), 2.94 (2H, t, J = 13.0 Hz), 1.60 [(1H,] br s), 1.48 (1H, br s), 1.15 (1H, br s), 0.94 (3H, d, J = 6.1 Hz), 0.00 (TMS, reference). [13C] NMR (100 MHz, CDC13) : [6] 129.41 (d), 127.46 (d), 125.96 (d), 125.83 (s), 56.12 (t), 51.23 (d), 48.73 (t), 46.45 (t), 20.05 (q), 0.00 (TMS, reference). IR (diffuse reflectance) 2964,2835, 2483 (w), 2350 (w), 2339 (w), 1956 (w), 1490,1025, 909,742 (s), 717,710 (s), 703 (s), 697 (s), 629, [CM-1.] HRMS [(EI)] calcd for [C24H26N2] 342.2096, found [342. 2101.] [a] [25D=-12° (C 1. 00, CH2CL2).] Anal. Calcd for [C24H26N2] : C, 84.17 ; H, 7.65 ; N, 8.18. Found: C, 84.12 ; H, 7.64 ; N, 7.94.
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; sodium carbonate; In water;
Example 26A (3R)-3-methyl-1-pyridin-2-ylpiperazine (R)-(-)-2-Methylpiperazine (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 a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1 N HCl solution were added to the water/ethyl acetate mixture with vigorous mixing. The layers were separated, and the combined aqueous phases were basified 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 chloroform containing a few drops of isopropyl alcohol (5*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.79 g (89percent 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)+.
89%
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; sodium carbonate; In water;
Example 26A (3R)-3-methyl-1-pyridin-2-ylpiperazine (R)-(-)-2-Methylpiperazine (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 a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1 N HCl solution were added to the water/ethyl acetate mixture with vigorous mixing. The layers were separated, and the combined aqueous phases were basified 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 chloroform containing a few drops of isopropyl alcohol (5*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.79 g (89percent 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, 8Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
89%
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; sodium carbonate; In water;
EXAMPLE 26A (3R)-3-methyl-1-pyridin-2-ylpiperazine (R)-(-)-2-Methylpiperazine (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 a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1 N HCl solution were added to the water/ethyl acetate mixture with vigorous mixing. The layers were separated, and the combined aqueous phases were basified 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 chloroform containing a few drops of isopropyl alcohol (5*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.79 g (89percent 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)+.
89%
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; sodium carbonate; In water;
EXAMPLE 26A (3R)-3-methyl-1-pyridin-2-ylpiperazine (R)-(-)-2-Methylpiperazine (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 a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1 N HCl solution were added to the water/ethyl acetate mixture with vigorous mixing. The layers were separated, and the combined aqueous phases were basified 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 chloroform containing a few drops of isopropyl alcohol (5*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.79 g (89percent 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)+.
89%
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; sodium carbonate; In water;
Example 26A (3R)-3-methyl-1-pyridin-2-ylpiperazine (R)-(-)-2-Methylpiperazine (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 a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1 N HCl solution were added to the water/ethyl acetate mixture with vigorous mixing. The layers were separated, and the combined aqueous phases were basified 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 chloroform containing a few drops of isopropyl alcohol (5*). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.79 g (89percent 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)+.
With triethylamine; In dimethyl sulfoxide; at 100℃; for 24h;
[3-DICHLOROPYRIDINE] (2.94 [G, 20.] 0 [MMOL),] [(R)-2-METHYLPIPERAZINE] (2.75 g, 27.5 mmol) (Commercially available from [SIGMA-ALDRICH,] St. Louis, [MO] (www. sigma- [ALDRICH.] [COM)),] and triethylamine (3. [04] g, 30 mmol) were dissolved in 15 mL of dimethylsulfoxide and the resulting mixture was heated at about [100C FOR ABOUT] 24 [ H. THE] reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and purified using a silica gel column eluted with a gradient elution (ethyl acetate to [2 : 1 ETHYL ] acetate : methanol) to provide Compound 1 [(N- (3-CHLOROPYRIDIN-2-YL)-PIPERAZINE) AS] a yellow liquid (90percent yield).
With potassium carbonate; In N,N-dimethyl acetamide; ethyl acetate;
Part A Synthesis of (R)-1-(3-Chloro-pyridin-2-yl)-3-methyl-piperazine: Dissolve 2,3-dichloropyridine (8.5 g, 0.057 moles) and (R)-(-)-2-methylpiperazine (5.75 g, 0.057 moles) in N,N-dimethylacetamide (125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (23.75 g, 0.172 moles) to this mixture and stir at 135-140° C. for 48 h. New spot noticed in TLC (5percent MeOH / CHCl3 / 1percent NEt3) along with absence of starting materials. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3*200 mL) and wash the combined organic extract with brine (2*150 mL). Dry over MgSO4, concentrate under vacuum to afford crude product (20.0 g) as orange yellow liquid. Distil the crude under high vacuum to afford pyridylpiperazine derivative as yellow viscous oil (10 g, bp 112-115° C. /0.1 torr). NMR (CDCl3): delta.. 1.1-1.12 (d, 3H, J=1.6 Hz), 2.50-2.53 (t, 1H), 2.83-2.87 (m, 1H), 3.06-3.08 (m, 3H), 3.67-3.75 (m, 2H), 6.80-6.82(dd, 1H), 7.56-7.58 (dd, 1H), 8.17-8.18 (dd, 1H).
With potassium carbonate; In ISOPROPYLAMIDE; at 135 - 140℃; for 48h;
Dissolve 2, 3-DICHLOROPYRIDINE (8. 5 g, 0. 057 moles) and (R)- (-)-2-METHYLPIPERAZINE (5. 75 g, 0. 057 moles) in DMA (125. 0 mL) under nitrogen atmosphere. Add anhydrous powdered K2C03 (23. 75 g, 0. 172 moles) to this mixture and stir at 135-140°C for 48 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3 x 200 mL) and wash the combined organic extract with brine (2 x 150 mL). Dry over MgS04, concentrate under vacuum to afford crude product as orange yellow liquid. Distil the crude under high vacuum to afford pyridylpiperazine derivative as yellow viscous oil.
With potassium carbonate; In ISOPROPYLAMIDE; at 135 - 140℃; for 48h;
Dissolve 2-CHLORO-3-TRIFLUOROMETHYLPYRIDINE (0. 057 moles) and (R)- (-)-2- methylpiperazine (5. 75 g, 0. 057 moles) in DMA (125. 0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (23. 75 g, 0. 172 moles) to this mixture and stir at 135-140°C for 48 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3 x 200 mL) and wash the combined organic extract with brine (2 x 150 mL). Dry over MGS04, concentrate under vacuum to afford crude product as orange yellow liquid. Distil the crude under high vacuum to afford the title compound.
Synthesis of (3R)-3-methyl-1-(phenyl(3-(trifluoromethyl)phenyl)-methyl)piperazine To a solution of (R)-(-)-2-methylpiperazine (2.2 g, 22 mmol) in CH3CN (20 mL) was added 1-(chloro(phenyl)methyl)-3-(trifluoromethyl)benzene (2.0 g, 7.4 mmol) and heated to 100° C. for 12 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3 or Na2SO4, filtered, and concentrated. The crude product was purified by ISCO using 0-20percent 2N NH3/MeOH solution in CH2Cl2 to give the title compound (2.00 g, 81percent yield) as oil. MS (ESI, pos. ion) m/z: 335.1 (M+1).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a stirred mixture of 4-fluoronitrobenzene (2.0 g, 0.014 mol, 1.0 eq) in DMF (50 mL) at rt, (R)-2-methylpiperazine (1.1 eq) and K2CO3 (3.0 eq) were added and stirred at rt for 16 h. After TLC showed completion of starting material, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 150 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulphate, and concentrated to provide crude residue. The crude was triturated with n-hexane and filtered to obtain (R)-3-methyl-l-(4-nitrophenyl)piperazine (2.6 g, 84percent) as yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 8.028 (d, 2H), 7.002 (d, 2H), 3.860 (m, 2 H), 2.952 (d, 1H), 2.887 (t, 1H), 2.790 (m, 2H), 2.450 (m, 1H), 2.331 (s, 1H), 1.023 (d, 3H).
(3R)-3-methyl-1-(2-pyridinyl)piperazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
> 99%
[1653] A solution of (R)-(-)-2-methylpiperazine (0.50 g, 0.005 mol, CAS 75336-86-6, Aldrich 39,716-4, 99percent) 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 a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1N Hydrochloric acid solution were added to the water/ethyl acetate mixture with vigorous mixing until all of the product was transferred to the aqueous phase. The layers were separated, and the combined aqueous phases concentrated under reduced pressure, and azeotroped with toluene/methanol (5.x.) to afford 1.29 g (>99percent yield) of 3-(R)-methyl-1-pyridin-2-yl-piperazine hydrobromide. 1H NMR (300 MHz, DMSO-d6) delta1.27 (d, J=6.6 Hz, 3H), 2.90 (dd, J=10.5, 14.1 Hz, 1H), 3.10 (m, 2H), 3.40 (m, 2H), 4.32 (m, 2H), 6.77 (dd, J=4.8, 6.9 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.64 (m, 1H), 8.15 (m, 1H), 8.63 (br s, 1H), 8.92 (br s, 1H); MS (ESI) m/e 178 (M+H)+.
With sodium hydroxide; In branched octane; water; at 80℃; for 2h;
(R)-2-methylpiperazine, L-tartrate from Example 4 in H20 (182 L), and Branched octanes (200 L) were added to a 4000 L reactor and stirred until dissolved. More branched octanes (530 L) were added to the 4000 L reactor followed by 50percent [NAOH] (1120 kg) at a temperature between [35°C] and [52°C.] The solution was heated to [80°C] and stirred [FOR 2H.] The solution was settled and the lower aqueous phase was transferred to the 4000 L receiver. The solution in the 4000 L reactor was cooled [TO-21°C] and filtered onto a 48"Nutsche filter sending the filtrate to a 1200 L reactor. The 4000 L reactor and 48"Nutsche filter were rinsed with branched octanes (300 L). The solids were dried with [25°C] nitrogen and collected to yield 24.9 kg (67percent) of the title compound [OF NLT] 99percent ee as determined by chiral HPLC assay. The aqueous solution in the 4000 L receiver was adjusted to pH 8.4 with acetic acid (812 kg) before disposal. The yield of the title compound according to D2, starting from (R)-2-methyl- piperazine, L-tartrate was 42percent. M. Pt. [91-93°C.] 'H NMR (400 MHz, [CDC13)] : [No. ] 2.97-2. 68 (6H, [M),] 2. [35] [(1H,] dd, J = 11.7, 10.2 Hz), 1.61 (2H, s), 1.00 (3H, d, J = 6.7 Hz), 0.00 (TMS, reference). [APOS;3C] NMR (100 MHz, CDC13) : [6] 54.14 (t), [51.] 89 (d), 47.43 (t), 46.46 (t), 20.08 (q), 0.00 (TMS, reference). IR (mull) 3220 (s, b), 2819 (s), 2748,2042 (w), 1995 (w), 1981 (w), 1328, 1279,1137, 1094,960, 859 (s), 845 (s), 795 (s), 621 (s), [CMAPOS;APOS;.] HRMS (FAB) calcd for [C5HZ2N2] [+HI] 101.1079, found 101.1080. [[A,] 25D = _17°] (c 0.85, [CH2CI2).] Anal. Calcd for [C5HI2N2] : C, 59.96 ; H, 12.07 ; N, 27.97. Found: C, 59.25 ; H, 11.71 ; N, 27. [64.]
alpha-Bromodiphenylmethane (1.23 g, 4.99 mmol) was added to a solution of [R]-2-methylpiperazine (500 mg, 4.99 mmol) in DMF (20 mL) and stirred overnight. EtOAc and 15percent NaOH were added and the layers were separated. The EtOAc layer was washed with 15percent NaOH, brine, dried over sodium sulfate and concentrated. The residue was purified via radial chromatography (EtOAc/hexanes) to give 565 mg 1-benzhydryl-5R-methyl-piperazine. M+H+(267).
With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 20℃;
Example 49; l-{2-[(2R)-4-benzhydryl-2-methylpiperazin-l-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2- one; Example 49A; (R)-l-benzhydryl-3-methylpiperazine; A solution of the dihydrochloride of i?-methylpiperazine (Tetrahedron Lett. 1994, 35, 16, 2533-2536)(0.42 g, 2.42 mmol) in N,JV-dimethylformamide (3 mL) was treated with bromodiphenylmethane (0.6 g, 2.42 mmol), potassium carbonate (1.17 g, 8.5 mmol), and a catalytic amount of potassium iodide. The resultant reaction mixture was then stirred at ambient temperature overnight. Then the reaction mixture was concentrated and partitioned between water/methylene chloride. The organic layer was dried over magnesium sulfate, concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak.(R). HR Cl 8 6um 6psiA Prep-Pak.(R). cartridge column (40mm x 100mm) using a gradient of 10percent to 100percent acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound.
To 6.4 g 1-(4-fluorophenyl)-ethyl bromine in 100 mL DMF was added the piperazine. The mixture was then stirred overnight at room temperature. The solution was evaporated and the residue was then filtrated on a small quantity of silica gel, washing with ethyl acetate and methanol. Purification was carried out using flash chromatography, CHCl3/MeOH/Et3N=90/8/2 (or AcOEt/MeOH=90/10). 6.2 g (90percent) of pure compound (mixture inseparable of two diasteromers) was obtained. M+H+(223).
With sodium carbonate; In ISOPROPYLAMIDE; at 110℃; for 16h;
Heat a mixture of 2, 3-DICHLORO-6-METHOXY-PYRIDINE (1. 0 g, 5. 62 mmol), 2- (R)- METHYLPIPERAZINE (1. 13 g, 11. 23 mmol), and NA2CO3 (596 mg, 5. 62 mmol) in DMA at 110C for 16 hours. Partition the mixture between EtOAc and water, dry (NA2S04) the organic layer and concentrate under reduced pressure. Filter the residue through a small pad of silica gel eluting with 90 : 10 : 1 (DCM : MeOH : NH40H). Concentrate under reduced pressure to give the title compound.
Stage #1: 2-chloro-5-methylpyridine; (2R)-methylpiperazine In ethanol at 180℃; for 0.0833333h; Microwave;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
95.95A
A solution of 2-chloro-5-methyl-pyridine (127 mg, 1 mmoles), (2R)-2-methyl-piperazine (200 mg, 2 mmoles) in EtOH (3 mL) was heated in microwave to 180° C. for 5 minutes. The mixture was cooled, concentrated under reduced pressure and partitioned with DCM and the saturated aqueous sodium bicarbonate layer. The aqueous solution was extracted three times with additional DCM. The combined organic extracts were washed twice with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound.
3-[(3R)-3-methylpiperazin-1-yl]-1,2-benzisoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In 2-ethoxy-ethanol; for 18.0h;Heating / reflux;
A solution of (2R)-2-methylpiperazine (0.13 g, 1.3 mmol), <strong>[16263-52-8]3-chloro-1,2-benzisoxazole</strong> (0.2 g, 1.3 mmol) and triethylamine (0.36 mL, 2.6 mmol) in ethoxyethanol (8 mL) was heated at reflux for 18 hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (20. mL) and washed with water (2 X 10 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a brown oil, 0.14 g. LRMS (APCI+): m/z [M+H]+ 218
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16.0h;
A solution of (R)-2-methylpiperazine (7 g, 70 mmol, Aldrich) in DCM (200 mL) and DIEA (6.7 mL, 38.5 mmol, Aldrich) was added benzyl chloroformate (5 mL, 35 mmol, Aldrich) dropwise at 0 C. The mixture was then warmed up to RT and was stirred for 16 h. The solvents were removed and the residue was purified on silica gel using ISCO Combiflash system with DCM/2M methanolic ammonia gradient to give the title compound as light yellow oil. MS (ESI, positive ion) m/z: 235 (M+1).
8-[(3R)-3-methylpiperazin-1-yl]imidazo[1,2-a]pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 3h;
A solution of (2R)-2-methylpiperazine (0.2 g, 1.95 mmol), <strong>[69214-33-1]8-chloroimidazo[1,2-a]pyrazine</strong> (0.2 g, 1.3 mmol) and diisopropylethylamine (0.45 mL, 2.6 mmol) in n-butanol (10 mL) was heated at 100 C for three hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:concentrated aqueous ammonia, 95 : 5 : 0.5 to afford the title compound as a pale orange solid, 0.16 g. LRMS (ES) : m/z [M+H]+ 218
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 16h;Heating / reflux;
Intermediate 17: (3R)-3-methyl-l-(4-propylphenyl)piperazine ;A mixture of (R)-2-methylpiperazine (3.00 g, 30.0 mmol, 1.0 eq), l-bromo-4-propylbenzene (6.27 g, 31.5 mmol, 1.05 eq.), (+/-)-BINAP (747 mg, 1.2 mmol, 0.04 eq.) and sodium tert-butoxide (4.32 g, 45.0 mmol, 1.5 eq.) in toluene (70 mL) was degassed for 15 min with N2. Palladium(II) acetate (337 mg, 1.5 mmol, 0.05 eq.) was then added at once. The reaction mixture was then heated to reflux for 16h then cooled to RT. The mixture was then filtered on a bed of cellite and washed with Et2O. The combined organic layers were then washed with H2O (3x), dried over MgSC>4, filtered and evaporated to give a dark brown oil. This residue was purified by chromatography on silicagel (DCM/MeOH 80/20) to give the title product as yellow oil (2.35 g, 36percent). M+(ESI): 219.2.
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 16h;Heating / reflux;
Intermediate 2: (3i?)-3-methyl-l-(4-trifluoromethoxyphenyl)-piperazine; To a mixture of (R)-2-methylpiperazine (3.0 g, 30 mmol), 4-trifluoromethoxy bromo benzene (6.6 g, 27.5 mmol) and sodium tert-butoxide (3.56 g, 37.5 mmol) in dry toluene (50 mL) under nitrogen atmosphere, were added Pd(OAc)2 (0.28 g, 12.5 mmol) followed by BINAP (0.62 g, 1 mmol) and refluxed for 16 h. Then the reaction mixture was concentrated and the crude compound was purified by clolumn chromatography on silica gel using chloroform and methanol as eluent to give the title compound as a dark brown liquid (3 g, 38 %).
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 130℃; for 0.5h;Microwave irradiation;
Intermediate 14;: 5-fluoro-2-[(3R)-3-methylpiperazin-l-yl]pyrimidine; HN,A solution of 2-chloro-5-fluoropyrimidine (239 mg, 1.80 mmol) and (R)-2-methylpiperazine (271 mg, 2.71mmol) in iPrOH (1 mL) and DIEA (617 uL) was heated in MW at 130°C for 30 min. Solvent was removed under reduced pressure and the crude (600 mg) was purified by chromatography on silica using DCM/methanol (9/1) as eluent to afford The title compound as a white solid (416 mg, quantitative). TLC- DCM / MeOH(8/2); R/ 0.3. JH NMR (DMSO-d6) 5 8.14 (s, 2H), 4.48 (d, J = 13.2 Hz, 2H), 4.33 (bra,1H), 2.98-3.13 (m, 2H), 2.83 (m, 2H), 2.67 (t, J = 12.7 Hz, 1H), 1.20 (m, 3H).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 140℃; for 14h;Microwave irradiation;
Intermediate 15;: (3R)-3-methyl-l-[5-(trifluoromethyl)pyridin-2-yl]piperazine; NA suspension of 2-bromo-5-trifluoromethyl-pyridine (2.37 g; 10.0 mmol; 1.0 eq.), (R)-2-methylpiperazine (2.00 g; 20.0 mmol; 2.0 eq.) and DIEA (1.94 g; 15.0 mmol; 1.5 eq.) in 4 mL of DMA was heated at 140°C for 14h. The mixture was cooled to room temperature. After evaporation of the solvent under vacuum, the residue was dissolved in a 1/1 mixture of DCM / Et2O. A 4N solution of HC1 was added (10 mL) then the resulting precipitate was collected and washed with Et2O. The solid was then poured to an aq. solution of NaOH (5N, 20 mL) and the resulting mixture was extracted with Et2O (3X). The combined organic layers were washed with brine, dried over MgSC>4, filtered and evaporated to give the title compound as an orange solid (1680 mg, 69percent) used without further purification for the next steps. M+(ESI): 246.3. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 99.9 percent).
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 16h;Heating / reflux;
Intermediate 5: (3J?)-l-(2-fluorophenyl)-3-methylpiperazine; FTo a mixture of l-bromo-2-fluorobenzene (5.0 g, 28.5 mmol), (R)-2-methylpiperazine (3.15 g, 31.3 mmol) and sodium-tert-butoxide (4.0 g, 42 mmol) in dry toluene (100 mL) under nitrogen was added Pd(OAc)2 (250 mg, 1.1 mmol) followed by BINAP (750 mg, 1.2 mmol). The reaction mixture was then refluxed for 16 h and cooled. The reaction mixture was washed with water, dried and evaporated to a residue. The residue was purified by chromatography using chloroform/methanol (8/2) as eluent to afford the title compound as a liquid (3.0 g, 55percent). TLC-Chloroform/Methanol (9/1); R/ 0.25. HPLC purity: 95percent.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 14h;
Intermediate 22: (3R)-1 -(4'-fluorobiphenyl-4-yl)-3-methylpiperazine; ,FA mixture of (R)-2-methylpiperazine (2.2 g, 22.1 mmol, 1.0 eq.), tris(dibenzylidene acetone)dipalladium(O) (607 mg, 0.66 mmol, 0.03 eq.) and (+/-)-BINAP (137 mg, 0.22 mmol; 0.01 eq.) in toluene was degassed 15 min under N2. 4-bromo^T-fluorobiphenyl (4.99 g, 19.9 mmol, 0.90 eq.) was added followed by sodium tert-butoxide (2.97 g, 30.9 mmol, 1.4 eq.). The resulting mixture was heated to 90°C for 14h. The reaction was cooled to room temperature, filtered on a bed of cellite and washed with Et2O. The combined organic layers were then washed with H2O (3x), dried over MgSO4, filtered and evaporated to give a dark brown oil. This residue was purified by chromatography on silicagel (DCM/MeOH 20/80) to give the title product as off white solid (3.0 g, 50percent) M+(ESI): 271.3. HPLC (Condition A), Rt: 2.8 min (HPLC purity: 99.8 percent).
(3R)-3-methyl-1-[4-(methylsulfonyl)phenyl]piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h;
Intermediate 26:; (3R)-3-methyl-l-[4-(methylsulfonyl)phenyl]piperazine; A mixture of 4-fluorophenyl methyl sulfone (2.00 g), (R)-2-methylpiperazine (2.30 g) and K2CO3 (3.20 g) in anhydrous DMF (80 mL) was heated at 100°C for 5 hours. The reaction mixture was filtered to remove salts and the solvent was evaporated under reduced pressure to give a yellow oil. Purification by flash chromatography (CHCls/MeOH) gave 1.36 g (47percent) of the title compound as a pale yellow solid. M^SI): 255.2. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 100 percent).
94.i i
i (R)-2-(3-Methylpiperazin-1-yl)-N-(quinolin-5-yl)acetamide The subtitle compound was prepared from 2-chloro-N-(quinolin-5-yl)acetamide (1 g) (J Indian Chem Soc, 1940, 17, 619-621) and (R)-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)
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 18h;Heating / reflux;
To a mixture of 1-bromo^-fluorobenzene (5.Og, 0.0285mol), (R)-2-methylpiperazine (3.15g, 0.0313mol) and sodium-tert-butoxide (4g, 0.042mol) in dry toluene (100 mL) under nitrogen was added Pd(OAc)2 (0.25g, 0.001 lmol) followed by BINAP (0.75g, 0.0012 mol). The reaction mixture was then refluxed for 18h and cooled down to rt. The reaction mixture 20 was washed with water, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude by chromatography on silica (chloroform :MeOH, 8:2) gave the title compound as a liquid (2.5g, 46percent yield). TLC: R/= 0.25 (Chloroform/MeOH: 9/1).
With Tri(p-tolyl)phosphine; sodium t-butanolate;palladium diacetate; In toluene; at 20 - 110℃;
To a 250 mL flask containing 100 mL toluene was added 2.45 g sodium t-butoxide (25.5 mmol, 1.5 equiv), 191 mg palladium acetate (0.85 mmol, 0.05 equiv) and 517 mg tri-/?-tolylphosphine (1.7 mmol, 0.1 equiv) under N:*. After stirring for 20 mm., 3.Og 1 -bromo-4-fluorobenzene (17.0 mmol, 1.0 equiv) and 1.71 g (/?)-2-methylpiperazine (17.0 mmol, 1.0 equiv) were added to the solution. The resulting mixture was placed into a preheated 110 0C bath. After stirring for 7 h, the mixture was cooled to room temperature and stirred overnight. The mixture was filtered though a plug of celite. The celite plug was washed with 2 x CH2Cl2. The organics were dried (MgSO4) and concentrated under reduced pressure. Flash chromatography of the residue (SiO2, 2percent MeOH/CH2Cl2 to 2percent MeOH/CH2Cl2 with 1percent NH4OH) gave the product as a light-browiti oil.
To a solution of (R)-methylpiperazine (400 mg) in dichloromethane (20 mL) at 0 0C was added di-tert-butyl dicarbonate (871 mg). The reaction was stirred at room <n="194"/>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 (R)-3-methyl-piperazine-l- carboxylic acid tert-butyl ester as a white solid (669 mg, 84%).
50%
In dichloromethane; at 0 - 20℃;
(R)-2-methylpiperazine (5.025 g, 50.2 mmol) was dissolved in DCM (100 mL). A solution of boc anhydride (5.47 g, 25.1 mmol) in DCM (50 mL) was added dropwise at 0 C. The reaction mixture was stirred at rt for 1 h. The solution was filtered and concentrated under reduced pressure. Water (100 mL) was added to the residue, which 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 5.04 g title compound (50%) as a solid. 1H NMR (300 MHz, CDCl3) delta ppm 1.03 (d, J=6.3 Hz, 3H) 1.45 (s, 9H) 1.56 (s, 1H) 2.30-2.46 (m, 1H) 2.65-2.72 (m, 1H) 2.74-2.76 (m, 2H) 2.93-2.95 (m, 1H) 3.93 (br s, 2H).
50%
In dichloromethane; at 0 - 20℃;
(R)-2-methylpiperazine (5.025 g, 50.2 mmol) was dissolved in DCM (100 mL). A solution of boc anhydride (5.47 g, 25.1 mmol) in DCM (50 mL) was added dropwise at 0 C. The reaction mixture was stirred at rt for 1 h. The solution was filtered and concentrated under reduced pressure. H2O (100 mL) was added to the residue, which 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 5.04 g Intermediate D (50%) as a solid. 1H NMR (300 MHz, CDCl3) delta ppm 1.03 (d, J=6.3 Hz, 3H) 1.45 (s, 9H) 1.56 (s, 1H) 2.30-2.46 (m, 1H) 2.65-2.72 (m, 1H) 2.74-2.76 (m, 2H) 2.93-2.95 (m, 1H) 3.93 (br s, 2H). Intermediate D is also commercially available from Lanzhou Boc Chemical Co.
With triethylamine; In hexane; dichloromethane; ethyl acetate;
Step 1: 3-(R)-Methyl-piperazine-1-carboxylic Acid Tert-Butyl Ester Triethylamine (3 g, 4.2 mL, 30 mmol) was added to a solution of (R)-2-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: 1.05 (3H, d), 1.45 (9H, s), 2.11 (1H, s), 2.37-2.44 (1H, m), 2.66-2.79 (3H, m), 2.93-2.96 (1H, m), 3.93 (2H, br s). ESI-MS m/z: 201(M+1).
In tetrahydrofuran; at 20℃; for 18h;
i) tert-Butyl (3/?)-3-methylpiperazine-l-carboxylate;To a solution of (2No.)-2-methylpiperazine (Ig) in THF (10ml) was added di-tert-butyldicarbonate (1.45g). The reaction mixture was allowed to stir at room temperaturefor 18h.The reaction mixture was then partitioned between DCM (100 ml) and HaO (100 ml). Theorganics were separated and the aqueous layer was re-extracted with DCM (2 x 150ml).Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compoundas a clear oil. Yield: 1. Ig'H NMR: (DMSO) 8 0.92 (d, 3H), 1.38 (s, 9H), 2.57-2.70 (m, 1H), 2.76-2.81 (m, 1H), 2.87-2.99 (m, 1H), 3.66-3.74 (m, 4H)
With triethylamine; In dichloromethane; at 0 - 20℃; for 1.75h;
To a 0 0C solution of (R)-2- methylpiperazine (5.0 g, 50 mmol, 1.0 equiv) in dry DCM (200 mL) was added triethylamine (21 mL, 150 mmol, 3 equiv) by syringe. A solution of BOC2O (10.4 g, 47.4 mmol, 0.95 equiv) was then added as a solution in dry DCM (100 mL) over the course of an hour. After stirring for an addition 15 min at 0 "C, the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then washed with aq. satd. NaHCO3 and brine. The resulting DCM solution was dried over sodium sulfate, filtered, and concentrated in vacuo, and used in the next step without further purification. The residue was dissolved in dry DCM (50 mL), and Et3N (21 mL, 150 mmol, 3 equiv) was added by syringe. To this room temperature solution was added CbzCI (8.4 mL, (>0 mmol, 1.2 equiv) dropwise by syringe. After stirring at room temperature for 30 minutes, the mixture was quenched by the addition of aq. satd. NaHCC<3. The solution was washed an additional time with aq. satd. NaHCO3, twice with aq. 1 N KHSO4, and twice with brine. The DCM layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (100 mL), and HCl (4 N in dioxane, 150 mL, 600 mmol, 12 equiv) was added dropwise by syringe. After 2 h, the reaction mixture was concentrated in vacuo. To the resulting solid was added EtOAc and 1 N NaOH. The aqueous layer was extracted twice with EtOAc, and the organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide (/?)-benzyl 2-methylpiperazine-l-carboxylate (5.3 g, 45%).
With triethylamine; In hexane; dichloromethane;
Step 1 3-(R)-Methyl-piperazine-1-carboxylic acid tert-butyl ester Triethylamine (3 g, 4.2 mL, 30 mmol) was added to a solution of (R)-2-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: 1.05 (3H, d), 1.45 (9H, s), 2.11 (1H, s), 2.37-2.44 (1H, m), 2.66-2.79 (3H, m), 2.93-2.96 (1H, m), 3.93 (2H, br s). ESI-MS m/z: 201 (M+1).
In chloroform; for 1h;
In a nitrogen atmosphere, 115 mL of di-tert-butyl dicarbonate was dropwise added to chloroform (500 mL) solution of 50.0 g of (R)-2-methylpiperazine, over 1 hour. The reaction liquid was washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate = 2/1) to obtain 63.5 g of the entitled compound as a colorless oily substance.
25 g
In dichloromethane; at 0℃; for 1h;
15g of compound 6,150 ml of dichloromethane was added to the reaction flask.Cool down to 0 ° C,Dissolve in 100 mL of dichloromethane16.5g of Boc-anhydride was added to the reaction flask and stirred for 1 hour.Point plate monitoring, after the reaction, filtering,The filtrate was spun dry, added with 100 mL of water, stirred, filtered, and the filtrate was added with saturated 10 g of potassium carbonate and stirred with methyl tert-butyl ether ether.Extract, dry over sodium sulfate, spin dry,Adding petroleum ether, stirring and crystallizing under cooling to obtain 25 g of compound 7;
To 6.4 g l-(4-fluororhohenyl)-ethyl bromine in 100 mL DMF was added the 2R- methylpiperazine. The mixture was then stirred overnight at room temperature. The solution was evaporated and the residue was then filtrated on a small quantity of silica gel, washing with ethyl acetate and methanol. Purification was carried out using flash chromatography, CHCl3/MeOH/Et3N=90/8/2 (or AcOEt/MeOH=90/10). 6.2 g (90 percent) of pure compound (mixture inseparable of two diasteromers) was obtained. M+H+(223).
3. l-(5-Bromo-3-chloro-pyridin-2-yl)-3-(R)-methyl-piperazine; Clf"'.Heat a solution of <strong>[160599-70-2]2,5-dibromo-3-chloro-pyridine</strong> (Chontech Inc.) (2.0 g) and (R)-2-methyl-piperazine (3.2 g, 31.9 mmol) in DMA at 130C for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (lx) and brine (lx), dry and concentrate under reduced pressure to give the title compound as a solid.
With modified hectorite-loaded ionic liquid; In dimethyl sulfoxide; at 100 - 110℃; for 8h;Inert atmosphere;
The organically modified hectorite-loaded ionic liquid material prepared by the first embodiment of the present invention (abbreviated as MHIL) is used as a catalyst for catalytic condensation to prepare an intermediate for the treatment of diabetes drugs 5-[(3R)-3-methylperazine Pyrazin-1-yl]pyridine-2-carbonitrile (CN 101400653A),The reaction is shown in Scheme3:5-bromo-2-cyanopyridine (10 mmol, 1.81 g) under nitrogen atmosphere,Catalyst MHIL (0.36g, 20wtpercent),(R)-(-)-2-methylpiperazine (1.3 g, 13 mmol) was placed in 20 ml of dimethyl sulfoxide at 100-110 ° C. After 8 h, the reaction liquid was HPLC-detected for substrate 5-bromine- 2-cyanopyridine was not detected. The catalyst was filtered to remove MHIL. The filtrate was added with 20 ml of a 3 Mpercent aqueous solution of methylamine, and then extracted twice with 20 ml of dichloromethane. The methyl chloride layer is concentrated under reduced pressure5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile 1.88 g, yield 93percent, HPLC purity 99.86percent, LC-MS: m/z = 203.1 [M +H].The organic modified hectorite-loaded ionic liquid material prepared by the invention (abbreviated as MHIL) is used as a catalyst for preparing an intermediate for the treatment of diabetes drugs 5-[(3R)-3-methylpiperazin-1-yl] Pyridine-2-carbonitrile does not require the addition of precious metal palladium as compared to CN 101400653A, and the yield is significantly improved.Although the embodiments of the present invention have been described in detail, it is understood that various changes, modifications and changes may be made in the embodiments of the present invention without departing from the spirit and scope of the invention.
39.1%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 0.583333h;Microwave irradiation;
Example 29V. 2-(3-(r(2J?')-4-(6-ri-amino-2.2.2-trifluoro-l-('trifluoromethvnethvnpyridin-3-vU- 2-meth ylpjperazin- 1 -yli sulfonyl ) phenyl*)- 1.1,1 -trifluoropropan-2-ol; Step A; A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2- cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalldium (0) (83.15 mg, 0.0908 mmol), rac-2,2'-bis(diphenylphosphino)-l,F-binaphtyl (169.37 mg, 0.272 mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at HO0C for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield 5-[(3lambda)-3- methylpiperazin-l-yl]pyridine-2-carbonitrile as brown color oil (1.15 g, 39.1percent yield).
39.1%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 0.583333h;Microwave irradiation;
Example 142-(3-[(2R)-4-{6-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridin-3-yl}-2-methylpiperazin-1-yl]sulfonyl}phenyl)-1,1,1-trifluoropropan-2-ol; Step 1A: A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2-cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalldium (0) (83.15 mg, 0.0908 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (169.37 mg, 0.272 mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile as brown color oil (1.15 g, 39.1percent yield).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃;Microwave irradiation;
EXAMPLE 16; Example 16A. 1.1.1 -trifluoro-2-f4-( ((2R)-2-methyl-4-r2-f trifluoromethvDphenyl'lpiperazin- 1 - yl 1 sulfonvOphenyl'lpropan-sigma-ol; Step 16A; A mixture of (R)-2-methyl-piperazine (300 mg, 2.99 mmol), 2-bromo benzotrifluoride (612 mg, 2.72 mmol), tris(dibenzylidineacetone)dipalldium (0) (24.72 mg, 0.027 mmol), rac-2,2'-bis(diphenylphosphino)-l,l'-binaphtyl (51.06 mg, 0.082 mmol) and sodium tert- butoxide (326.77 mg, 3.4 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 1 1O0C for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated at (R)-2- methyl-piperazine (1.0 g, 9.98 mmol). Reaction mixtures were combined, diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-3-methyI-l -(2- trifluoromethyl-phenyO-piperazine as yellow oil (1.23 g, 39.6percent yield). IH NMR (400 MHz, CHLOROFORM-D) delta ppm 1.07 (d, J=6.32 Hz, 3 H) 2.41 - 2.51 (m, 1 H) 2.74 - 2.84 (m, 1 H) <n="157"/>2.90 - 2.98 (m, 2 H) 3.00 - 3.13 (m, 3 H) 7.18 - 7.25 (m, 1 H) 7.35 (d, J=8.08 Hz, 1 H) 7.47 - 7.55 (m, 1 H) 7.62 (d, J=7.83 Hz, 1 H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 105℃; for 3.5h;Inert atmosphere;
Step IA: A mixture of (R)-2-methyl-piperazine (25.0 g, 250 mmol), 2-bromo 5- fluoro benzotrifluoride (55.1 g, 227 mmol), tris(dibenzylidineacetone)dipalldium (0) (2.08g, 2.27 mmol), rac-2,2'-bis(diphenylphosphino)-l,r-binaphthyl (4.24 g, 6.81 mmol) and sodium tert-butoxide (27.3 g, 280 mmol) was mixed and purged with N2. Anhydrous toluene (500 mL) was added and purged with N2 again. The resulting mixture was heated in an oil bath at 105 0C under N2 for 3.5 hours. After cooling, the reaction mixture was concentrated and then filtered through a pad of Celite, washed with Et2O. The organic layer was concentrated, diluted with Et2O (500 mL), filtered through a pad of Celite again, and washed with IN aq. HCl (2 x 150 mL). The aqueous layer was basified with NaOH at 0 0C (pH = -10) and then was extracted with Et2O (3 x 200 mL). The combined organic layer was dried over MgSO4 and concentrated under vacuum to give (3i?)-l-[4- fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine as a brown oil (58.5 g, 98%), which was used without further purification.
33.6 - 82%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100 - 110℃; for 3 - 5h;Product distribution / selectivity;
EXAMPLE 29; Example 29A; Step 1; (R)-2-methyl-piperazine (3.5 g, 34.9 mmol), 2-bromo-5-fluoro benzotri fluoride (7.74 g, 31.7 mmol), BlNAP (0.59 g, 0.95 mmol), tBuONa (4.58 g, 47.65 mmol) and Pd2(dba)3 (0.29 g, 0.32 mmol) were mixed in the flask and purged with N2. Anhydrous toluene (50 mL) was added and purged with N2 again. The resulting mixture was heated in an oil bath at 1000C under N2 for 3 hours. The mixture was cooled to room temperature, diluted with dichloromethane (150 mL), washed with H2O (30 mL) first, then washed with saturated brine (30 mL). The combined organic layer was dried over Na2SO4, concentrated down under reduced pressure to give a brown color liquid as crude. The crude product was purified on silica gel column eluted with 5-10% MeOH in DCM to give (3lambda)-l-[4-fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine as a light yellow oil (6.85 g, 82%).; Example 29AX. 3-(((2R)-4-r4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin-l - yl ) sulfonvDphenol; Step A; (R)-2-methyl-piperazine (3.88 g, 38.70 mmol), 2-bromo, 5-fluoro benzotrifluoride (8.55 g, 35.18 mmol), tris(dibenzylidineacetone)dipalldium (0) (32.0 mg g, 0.35 mmol), rac-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (657.0 mg, 1.06 mmol) and sodium tert- butoxide (5.07 g, 52.77 mmol) were charged to a reaction flask. Toluene (40 mL) was introduced <n="195"/>under nitrogen atmosphere and the reaction mixture was heated up at 11O0C for 5.0 hours. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with water, saturated brine then dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-I -(4-fluoro-2- (trifluoromethyl)phenyl)-3-methylpiperazine as a light brown oil (3.1 g, 33.6% yield).
With sodium hydroxide; In water; at 25 - 60℃; for 0.166667h;
(3R)-3-methvM-(phenylcarbonothioyl)piperazine; A mixture of 2.8 grams (28 mmol) of (f?J-2-methylpiperaziotane and 6.0 grams (28. mmol) of S-(thiobenzoyl)thioglycolic acid was suspended in a solution of 1.6 g (40 mmol) NaOH in 50 mL of distilled water. The mixture was stirred for 5 minutes at 25 0C, and then for 5 minutes at 60 0C. The mixture was copied to 25 0C, and the ivory precipitate was collected by filtration. It was washed with distilled water, and dried in a stream of air. After further drying under high vacuum overnight there was obtained 5.1 grams of a white solid (80percent). 1HNMR (CDCI3): 7.35 - 7.20 (m, 5 H),.6.50 - 5.45 (m. 1 H), 4.80 - 4.65 (m, 1 H), 3.90 - 3.70 (m, 1 H), 3.30 - 2.70 (m, 5H)1 1.20 (d, J = 7 Hz, 1.5 H), 0.95 (d, J = 7 Hz, 1.5H).
b) Synthesis of (R)-4-(3-methylpiperazine-1-yl)thiazol 10.0 g (100 mmol) (R)-2-methylpiperazine were fused at 100 C. 2.7 g (16.8 mmol) <strong>[34259-99-9]4-bromothiazol</strong> was added in portions to this fusion over a period of 2 h. Stirring was subsequently performed for 18 h at 100 C. After cooling to RT, the residue was received in 10% aq. hydrochloric acid and washed with AE. Alkalic adjustment was subsequently performed with a 10% aq. NaOH sol. (pH>12) and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated in a vacuum. CC (SiO2, DCM/MeOH 9:1) was performed with the residue, whereby 277 mg (1.5 mmol, 9%) (R)-4-(3-methylpiperazine-1-yl)thiazol was obtained.
With potassium carbonate; In acetonitrile; at 20 - 60℃; for 2h;
To a mixture of 6-chloropyridine-3-carbonitrile (10 g, 0.06 mol) and (2R)-2-methylpiperazine(6.35 g, 0.06 mol) in acetonitrile (80 mL), K2C03 (12.0 g, 0.09 mol) was added at RT. Theresulting mixture was stirred at 60°C for 2 h (TLC indicated complete consumption ofstarting material). The reaction was brought toRT, quenched with water (150 mL) andextracted with EtOAc (3 x 80 mL). The combined organic extracts were dried over anhydrousNa2S04 and concentrated under reduced pressure. The residue was purified by columnchromatography (100-200 silica gel, 5percent MeOH-DCM) to afford 6-[(3R)-3-methylpiperazine-1-yl]-pyridine-3-carbonitrile (10.0 g, 69percent yield).
59%
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 36h;
Triethylamine (5.51 g, 4 mL, 54.6 mmol, 2.7 eq) is added to a solution of 6-chloro- nicotinonitrile (2.76 g, 20 mmol, 1 eq), (i?)-2-methyl- piperazine (2.0Og, 20 mmol, 1 eq) in DMF (15 mL), and the resulting solution is stirred at rt for 36 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 (2.3 g, 59percent). IH NMR (400 MHz, CHLOROFORM-*/) delta ppm 8.32 (d, J=2.40 Hz, 1 H), 7.52 (dd, J=9.09, 2.27 Hz, 1 H), 6.52 (d, J=8.97 Hz, 1 H), 4.14 - 4.24 (m, 2 H), 3.01 - 3.07 (m, 1 H), 2.72 - 2.94 (m, 3 H), 2.52 (dd, J=12.76, 10.36 Hz, 1 H), 1.07 (d, J=6.32 Hz, 3 H).
With sodium carbonate; In 1,4-dioxane; at 150℃; for 0.5h;Sealed vial; Microwave irradiation;
Solid Na2CO3 (200 mg, 1.9 mmol, 1.9 eq) is added to a solution of l-benzyl-4- chlorophthalazine (250 mg, 0.98 mmol, 1 eq) and (i?)-2-methyl-piperazine (400 mg, 4.0 mmol, 4.0 eq) in dioxane (5 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 150 0C (high absorption setting) for 30 minutes. The reaction mixture is filtered and concentrated, then diluted with EtOAc (50 mL) and water (15 mL). The organic fraction washed with water and then brine, then is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the title compound as a white solid (180 mg, 58 percent yield).IH NMR (400 MHz, CHLOROFORM-^) delta ppm 8.08 (d, J=7.07 Hz, 1 H) 8.00 (d, J=7.71 Hz, 1 H) 7.69 - 7.79 (m, 2 H) 7.34 - 7.39 (m, 2 H) 7.25 - 7.32 (m, 2 H) 7.20 (d, J=7.20 Hz, 1 H) 4.61 - 4.65 (m, 2 H) 3.76 - 3.82 (m, 2 H) 3.13 - 3.30 (m, 4 H) 2.85 (dd, ./=12.63, 10.23 Hz, 1 H) 1.17 (d, J=6.32 Hz, 3 H) MS (m/z, MH+): meas. 319.1
Example 43.1: 2-((R)-3-Methyl-piperazin-l -yl)-nicotinonitrile. A mixture of (R)-2-methyl piperazine (507 mg, 5.06 mmol), 2-chloro-nicotinonitrile (1.05 g, 7.6 mmol), triethylaniine (2 mL, 14.3 mmol) and tetrahydrofuran (8 mL) was heated at 80° C overnight. The reaction mixture was cooled to room temperature and aqueous saturated sodium bicarbonate (75 mL) was added. The mixture was extracted with dichloromethane (3x200 mL) and the combined organic layer washed with water (75 mL), washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel using dichloromethane: 2M ammonia in methanol (95:5) to give 2- ((R)-3-methyl-piperazin-l-yl)-nicotinonitrile (964 mg, 94 percent). 1H NMR (300 MHz, CDCl3): delta(ppm) 8.34 (dd, IH), 7.77 (dd, IH), 6.74 (m, IH), 4.27 (m, 2H), 3.08 (m, 4H), 2.70 (m, IH), 1.15 (d, 3H).
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;
A mixture of <strong>[622392-04-5]2-bromo-5-iodopyrazine</strong> (200mg, 0.704mmol), cesium carbonate (400mg, 1.23mmol) and 2R methyl piperazine( 85mg,0.85mmol) in DMF (10ml) was stirred at 100C overnight. The reaction was cooled and solvent evaporated .Water (100ml) was added and insoluble solid was filtered, then dissolved in MeCI2 (100ml), <n="252"/>dried over Na2SO4, filtered and solvent evaporated yielding product (205mg, 95%) Mass Spec (MH, 305)
95%
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;
A mixture of <strong>[622392-04-5]2-bromo-5-iodopyrazine</strong> (200mg, 0.704mmol), cesium carbonate (400mg, 1.23mmol) and 2R methyl piperazine (85mg, 0.85mmol) in DMF (1 OmI) was stirred at 1000C overnight. The reaction was cooled and solvent evaporated.Water (100ml) was added and insoluble solid was filtered, then dissolved in MeCb (100ml), dried over Na2SO4, filtered and solvent evaporated yielding product (205mg, 95%)
With sodium hydrogencarbonate; In water; acetone; at 20℃; for 17h;
(R)-2-methylpiperazine (13.85 g, 138 mmol) and sodium bicarbonate (52.3 g, 622 mmol) were partially dissolved in a mixture of water (182 ml) and acetone (112 ml). A solution of benzoyl chloride (17.7 ml, 152 mmol) in acetone (56 ml) was added dropwise over 1 hour with vigorous stirring. After stirring for 16 hours at RT, the acetone was stripped on the rotovap, water (400 ml) was added, and the solution acidified (6M HCl) to a pH less than 2. The aqueous phase was washed three times with dichloromethane (200 ml) and then 5M sodium hydroxide was added to bring pH over 12. The resulting solution was extracted three times with dichloromethane (200 ml), dried (MgSO4) and evaporated to give (R)-(3- methylpiperazin-l-yl)(phenyl)methanone 62 as a yellow oil, 15.1 g (54percent of theoretical). LC/MS m/z = 205 (M+H+).
With sodium hydrogencarbonate; In water; acetone; at 0℃; for 17h;
EXAMPLE 26 Preparation of (R)-(3-methylpiperazin-1-yl)(phenyl)methanone (JK-22) (R)-2-methylpiperazine (13.85 g, 138 mmol), and sodium bicarbonate (52.3 g, 622 mmol) were dissolved/suspended in water (182 mL) and acetone (112 mL). The flask was cooled in an ice bath and a solution of benzoyl chloride (17.7 mL, 152 mmol) in acetone (56 mL) was added drop-wise over 1 hour. After 16 hours the acetone was removed on the rotovap. Water (400 mL) was added and the resulting mixture acidified using 6 M HCl to pH <2. The aqueous layer was washed with 200 mL CH2Cl2 three times. Aqueous sodium hydroxide (5M) was added to pH>12, and this solution was extracted three times with 200 mL of CH2Cl2. The combined organics were dried (MgSO4) and evaporated to give a thick yellow oil. MS (M+H)+=205.1
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
I. Preparation of intermediate compounds IV; Preparation Example 1 : (R)-4-{5-[4-((S)-2-Fluoro-1-methyl-ethyl)-benzenesulfonyl- aminoj-theta-methyl-pyridin^-ylj^-methyl-piperazine-i-carboxylic acid tert-butyl ester; 1.1 (R)-2-Methyl-4-(6-methyl-5-nitro-pyridin-2-yl)-piperazine; 0.72 g of (R)-2-methyl-piperazine (4.17 mmol) were dissolved in 10 ml. of N, N- dimethylformamide. 1.165 g of potassium carbonate (8.43 mmol) and 0.44 g of <strong>[22280-60-0]6-chloro-2-methyl-3-nitro-pyridine</strong> were added and the mixture was stirred for 16 h at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between water and diethyl ether. The aqueous layer was extracted with diethyl ether and the combined organic phases washed with water, dried over sodium sulfate, filtered and the filtrate was evaporated to dryness to yield 0.85 g of the titel compound.ESI-MS: 237.1 [M+H]+
Example 2; Synthesis of 2-((/?)-2-methyl-4-(2-phenylcyclohexyl)piperazin-l-yl)acetic acid dihydrochloride <n="72"/>Step 1A mixture of 2-phenylcyclohexanone (1.74 g, 9.99 mmol), (/?)-2-methylpiperazine (3.00 g, 30.0 mmol) and titanium (4+) isopropoxide (5.85 ml, 20.0 mmol) was heated at 80 0C under N2 overnight. After cooling to rt, 10 mL of MeOH was added followed by slow addition of NaBH4 (1.13 g, 30.0 mmol). After stirring for 30 min, the solvent was evaporated and the residue was redisolved in EtOAc. The solution was treated with 15 g OfNaHCO3 and 1 mL of water to generate slurry. This was filtered with large excess of EtOAc. The solvent was evaporated and the residue was submitted to flash chromatography (SiO2, DCM to DCM/MEOH = 100:5 to 100:10 to 100:20) to give (3lambda)-3 -methyl- 1 -(2-phenylcyclohexyl)- piperazine (1.82 g, 70.5percent yield) as a colorless oil.
Example 1; Synthesis of 2-((lambda)-2-methyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)- piperazin-l-yl)acetic acid <n="71"/>Step 1A mixture of 1 -benzosuberone (0.803 ml, 5.01 mmol), (/?)-2-methylpiperazine (1.505 g, 15 mmol) in titanium (4+) isopropoxide (4.399 ml, 15 mmol) was heated at 800C overnight. After cooling to RT, the reaction mixture was diluted with 30 mL of MeOH and sodium borohydride (0.529 ml, 15 mmol) was slowly added. After stirring at rt for 20 min, the solvent was evaporated to dryness. The residue was redissolved in 50 mL of EtOAc and to this solution was added 1O g OfNaHCO3 and 0.5 mL of water to generate a white slurry. After stirring at rt for 2 h, the mixture was filtered with the help of excess EtOAc and the filtrate was evaporated to dryness. Column chromatography (SiO2, DCM/MeOH = 100:5 to 100:10 to 100:15 to 100:20) gave (3lambda)-3-methyl-l-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)piperazine (860 mg, 70percent yield) as an off white gum.
[(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
In water High Pressure; heating mixt. of zinc compd., acetic acid deriv., methylpiperazine and water at 160°C for 120 h; isolation of ppt., rinsing with water under ultrasonic conditions, elem.anal.;
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 48h;
Solid K2CO3 (10 g, 72.4 mmol, 1.8 eq) is added to a solution of (R)-2-methyl-piperazine (4.00 g, 40 mmol, 1 eq) and <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (8 g, 45.2 mml, 1.1 eq) in DMF (50 mL), and the resulting solution is stirred at 60° C. for 48 h. The reaction mixture is concentrated to 1/2 volume under reduced pressure and the minimum water (ca. 15 mL) required to dissolve the solid salts is added, followed by the addition of dichloromethane (100 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure, then purified by silica gel column chromatography (2percent-20percent MeOH/CH2Cl2) to yield the desired compound as a white solid (4.7 g, 49percent).1H NMR (400 MHz, CDCl3) delta=3.08-3.21 (m, 2H), 2.73-2.92 (m, 4H,) 2.47 (dd, J=12.4 Hz, 10.2 Hz, 1H), 2.13 (s, 3H), 2.07 (s, 3H), 0.93 (d, J=6.3 Hz, 3H).HR MS (m/z, MH+): meas. 241.1218.
Combine <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (100 mg, 0.554 mmol), (R)-2-methylpiperazine (85 mg, 0.831 mmol), potassium carbonate (383 mg, 2.77 mmol) and DMF (1 mL) in vial. Heat in the microwave at 120° C. for 3.25 h. Add 2-chloro-5-trifluoromethylpyridine (181 mg, 0.997 mmol) and heat at 180° C. for 30 min. The crude reaction is purified directly by flash chromatography on silica gel (0-40percent EtOAc in heptanes) to afford the title compound as a light yellow solid (78 mg, 37percent).MS (m/z, MH+) meas. 386.4
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 170℃; for 0.5h;microwave irradiation; sealed vial;
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-3-yl-methanone (1.2 g, 4.84 mmol) and (R)-2-methyl-piperazine (485 mg, 4.84 mmol) are added to a microwave vial followed by NMP (17 mL) and triethylamine (2.01 mL, 14.49 mmol). The vial is sealed and irradiated in the microwave at 170° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20percent methanol in CH2Cl2). The resulting oil is co-evaporated with CH2Cl2 and heptane to afford the title compound as a powder (1350 mg, 90percent). 1H NMR (400 MHz, DMSO-d6) delta=9.56 (br s, 1H), 8.96 (s, 1H), 8.84-8.86 (m, 1H), 8.21-8.24 (m, 1H), 7.60-7.63 (m, 1H), 3.72 (s, 1H), 3.69 (s, 1H), 3.45-3.50 (m, 1H), 3.26-3.31 (m, 4H), 2.30 (s, 6H), 1.32 (d, J=6.5 Hz, 3H).
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;microwave irradiation; sealed vial;
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-2-yl-methanone (550 mg, 2.22 mmol), (R)-2-methyl-piperazine (320 mg, 3.20 mmol) are added into a microwave vial followed by NMP (6 mL) and triethylamine (0.92 mL, 6.66 mmol). The vial is sealed and irradiated in the microwave at 180° C. for 1 h. The crude material is directly purified via flash chromatography on silica gel (20-70percent methanol in CH2Cl2) to afford the title compound (671 mg, 97percent). 1H NMR (400 MHz, DMSO-d6) delta=9.57 (br s, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.10-8.17 (m, 2H), 7.69-7.73 (m, 1H), 3.65 (m, 1H), 3.62 (m, 1H), 3.45-3.50 (m, 1H), 3.12-3.33 (m, 4H), 2.29 (s, 3H), 2.15 (s, 3H), 1.32 (d, J=6.5 Hz, 3H).
To a solution of 3-benzyl-6-chloro-4,5-dimethylpyridazine (100 mg, 0.41 mmol) in NMP (2 mL) is added 2-(R)-methyl-piperazine (62 mg, 0.61 mmol). The reaction mixture is heated at 190° C. for 4 h in a microwave reactor. It is cooled down to rt, diluted with DCM, washed with aq. NaHCO3 solution and the organic layers are removed to afford the crude product. Flash chromatography of the crude product with EtOAc/heptane (20percent to 50percent) and then MeOH/DCM (5percent to 20percent) provides the product as a yellow solid after removal of the solvents (74 mg, 61percent).1H NMR (400 MHz, DMSO-d6) delta=7.22-7.34 (m, 2H), 7.11-7.22 (m, 3H), 4.22 (s, 2H), 3.13-3.26 (m, 2H), 2.81-2.99 (m, 3H), 2.70-2.80 (m, 1H), 2.38-2.48 (m, 1H), 2.15 (s, 3H), 2.08 (s, 3H), 1.00 (d, J=6.5 Hz, 3H).HR MS (m/z, MH+) meas. 297.2089.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 1h;Inert atmosphere;
Example 1] Synthesis of compound (I-40) a) Synthesis compound 3 [Show Image] [Show Image] Under the nitrogen atmosphere, toluene (7.5 ml) was added to a commercially available compound 2 (1.50 g, 7.30 mmol), a commercially available compound 1 (1.50 g, 7-30 mmol), and sodium tert-butoxide (842 mg, 8.76 mmol) were added, and the system was degassed, and replaced with nitrogen. Xantphos (127 mg, 0.22 mmol) and Pd2(dba)3 (67 mg, 0.67 mmol) were added to react them at 100C for 1 hour. Toluene (8 ml) was added to dilute the reaction, and this was filtered using Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a compound 3 (1.27 g, yield 77%). 1H-NMR (CDCl3 / TMS) deltappm: 1.13 (d, J = 6.2Hz, 3H), 1.57 (s, 1H), 2.28-2.37 (m, 1H), 2.35 (s, 3H), 2.67 (dt, J = 3.5, 11.6Hz, 1H), 2.92-3.15 (m, 3H), 3.46 (d, J = 11.6Hz, 2H), 6.69 (dd, J = 8.9, 2.7Hz, 1H), 6.78 (d, J = 2.7Hz, 1H), 7.19 (d, J = 8.9Hz, 1H).
With MP-carbonate; In isopropyl alcohol; at 150℃; for 1.5h;Microwave irradiation; Sealed tube;
2.61 Example 61 (Prepared according to Scheme 14); (R)-3-Chloro-2-(3-methyl-4-(4-(trimethylsilyl)phenylcarbamoyl)piperazin-l-yl)pyridine 1 -oxide; 2,3-Dichloropyridine 1-oxide (CAS 53976-65-1) (l .l δmmol), (R)-2-methylpiperazine (l.lδmmol) and MP- Carbonate (2.36mmol) were combined in propan-2-ol (5 ml) in a microwave tube, sealed and heated in the microwave to 1500C for 90 minutes. The reaction mixture was cooled, filtered and evaporated to leave a brown gum (252 mg), which was determined to be a mixture of (R)-3-chloro-2-(3-methylpiperazin-l- yl)pyridine 1-oxide (67%) and starting 2,3-dichloropyridine 1-oxide (33%).The crude intermediate (239 mg) was then combined with Intermediate 1 (0.77mmol), TEA (lmmol) and 4- dimethylaminopyridine (catalytic) in EtOH (4 ml), sealed in a microwave vessel and heated to 1000C, for 30 minutes. The reaction mixture was cooled and evaporated and the residue partitioned between ethyl acetate (30 ml) and 0.5 M Na2CO3 (20 ml). The organic layer was washed with water (10 ml), dilute citric acid (10 ml), water (10 ml), saturated sodium bicarbonate (10 ml), brine (20 ml), dried over Na2SO4 and evaporated to leave an amber gum. This crude product was then purified by flash chromatography (2-7% MeOH/DCM) and the combined product fractions freeze-dried yielding the title compound as a white solid (0.25mmol). ES+ 419, 421. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, 1 H), 7.41 - 7.52 (m, 2 H), 7.33 - 7.41 (m, 2 H), 7.28 - 7.33 (m, 1 H), 6.84 - 7.03 (m, 1 H), 6.41 (s, 1 H), 4.33 (br. s., 1 H), 2.90 - 4.10 (m, 6 H), 1.43 (d, 3 H), 0.25 (s, 9 H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 107℃; for 3h;Inert atmosphere;
Step 5 A: A mixture of (R)-2-methyl-piperazine (6.0 g, 59.9 mmol), 4-chloro-3- trifluoromethyl-benzonitrile (11.2 g, 54.5 mmol), tris(dibenzylidineacetone)dipalldium (0) (0.499 g, 0.545 mmol), rac-2,2'-bis(diphenylphosphino)-l,l '-binaphthyl (1.02 g, 1.635 mmol)and sodium tert-butoxide (6.55 g, 68.12 mmol) was mixed and purged with N2. Anhydrous toluene (75 mL) was added and the resultant mixture was purged with N2 again. The resultant mixture was heated in an oil bath at 107 0C under N2 for 3 hours. After cooling, the reaction mixture was diluted with DCM (200 mL), washed with H2O (50 mL), and washed with saturated brine (50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to give a dark brown liquid. The crude product was purified using a SiO2 gel column, eluting with 5-7percent MeOH in DCM to give 4-[(3i?)-3-methylpiperazin-l-yl]-3-(trifluoromethyl)benzonitrile as a brownish red color oil (l 1.2 g, 76.2percent).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 3h;
Example 27 To a solution of Compound B (0.2 g, 0.54 mmol) in acetonitrile (5 mL) at room temperature were added diisopropylethylamine (0.4 mL, 2.3 mmol) and (R)-(-)-2-methylpiperazine (0.081 g, 0.81 mmol) and the reaction mixture was heated to 80° C. On heating, the reaction mixture became clear and after 15 min commencement of precipitation of solid was observed. Heating was continued for 3 hr and then the reaction mixture was cooled. The solid obtained was collected by filtration, washed with acetonitrile and dried under vacuum. LC/MS: (M+H)+: 435. An NMR spectrum is provided in FIG. 27.Yield: 0.13 g (55percent).
Example 106: Synthesis of 6-(( R )-4-(4-Cyanophenyl)-2-methylpiperazin-1-yl)- N -(( E )-5-hydroxyadamantan-2-yl)picolinamide [300] [301] Step 1: Synthesis of ( R )-4-(3-methylpiperazin-1-yl)benzonitrile [302] 4-Bromobenzonitrile (200 mg, 1.099 mmol), (R)-2-methylpiperazine (121 mg, 1.209 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), BINAP (41 mg, 0.066 mmol), and sodium-tert-butoxide (211 mg, 2.199 mmol) were suspended in toluene (5 ml), and then the resulting liquid was stirred at 100oC under nitrogen stream for 5 hours. 1N aqueous HCl solution (20 ml) was added to the resulting reaction liquid, followed by extraction with MC (10 ml x 2). The aqueous layer was neutralized by addition of 5N aqueous NaOH solution, followed by extraction with 5percent MeOH/MC (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (10percent MeOH/MC), to obtain 152 mg of pale yellow oil (69percent).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); ruphos; In toluene; at 100℃; for 12h;sealed vial;
A 20 mL vial was charged with (R)-2-methylpiperazine (0.357 g, 3.56 mmol, Sigma-Aldrich, St. Louis, MO), 2-(4-bromophenyl)-l, 1,1, 3,3,3- hexafluoropropan-2-ol (1.00 g, 3.10 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), sodium tert-butoxide (0.625 g, 6.50 mmol) and 6 mL of toluene. To this was added dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.022 g, 0.046 mmol, Strem Chemical Inc, Newburyport, MA),tris(dibenzylideneacetone)dipalladium (0) (0.014 g, 0.015 mmol, Strem Chemical Inc, Newburyport, MA). The vial was sealed in heated at 100 C for 12 h. After that time, the mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were dried (MgS04) and concentrated to give 1,1,1 ,3 ,3 ,3-hexafluoro-2-(4-((3R)-3-methyl- 1 -piperazinyl)phenyl)-2- propanol (0.950 g) as an oil which was used without purification.
Example 3535-A. (l?)-6-Benzyl-2-chloro-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-l-yl)-5,6,7,8- tetr ahydr opyrido [4 ,3-d] pyrimidine.Isopropanol (80 mL) was added to <strong>[778574-06-4]<strong>[778574-06-4]6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimid</strong>ine</strong> (CASNo. 778574-06-4 2.5 g, 8.50 mmol) followed by triethylamine (3.55 mL, 25.5 mmol) and (R)-2- methylpiperazine (1.28 g, 12.8 mmol). The mixture was heated at 50 C for 6.5 hours and then cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted one additional time with dichloromethane. The organic layers were combined dried over Na2S04, filtered, and concentrated. A portion of the resulting residue (1.3g) was then dissolved in dichloromethane (25 mL) and charged with triethylamine (1.2 mL, 8.7 mmol). The mixture was placed at 0 C and then 2-nitrobenzene-l-sulfonyl chloride (0.97 g, 4.4 mmol) was added. The mixture was stirred at 0 C for 30 minutes then warmed to room temperature and stirred an additional 1 hour. The mixture was then quenched with saturated aqueous sodium bicarbonate and stirred for 1 hour. The mixture was then further diluted with dichloromethane and saturated aqueous sodium bicarbonate and the layers separated. The aqueous layer was extracted one additional time with dichloromethane. The organic layers were combined dried over Na2S04, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (50-85% ethyl acetate/heptanes) to afford: (R)-6-benzyl-2-chloro-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-l-yl)-. tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 686.4 (M+H)+.
With triethylamine; In N,N-dimethyl-formamide; at 165℃; for 4h;Microwave irradiation; Sealed tube;
STEP A: (i?)-l-(5-bromo-6-methylpyridin-2-yl)-3-methylpiperazine [1136] In a 10 mL microwave vial equipped with a magnetic stir bar were mixed 3-bromo- 6-chloro-2-methylpyridine (515 mg, 2.496 mmol), (i?)-2-methylpiperazine (250 mg, 2.496 mmol), and Et3N (1.044 mL, 7.49 mmol) in DMF (4 mL). The resulting yellow suspension was heated in a microwave reactor to 165C for 4 hours. The reaction mixture was subsequently partitioned between 0.25N HC1 (40 mL) and EtOAc (40 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (40 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2S04, filtered, and concentrated. The residue was purified using flash chromatography (12 g column) eluting with a gradient of 0-100% EtOAc in heptanes and then 0-20% MeOH in DCM. The pure fractions were combined and concentrated to give the title compound as a clear syrup (240 mg, 35.6%>).
(R)-4-((3-methylpiperazin-1-yl)methyl)-N-(4-(trifluoromethyl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64.4%
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 50°C 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, 91.5percent).
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 77percent).
(R)-2-methyl-1,4-bis(4-vinylbenzyl)piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.5%
With potassium carbonate; In chloroform; at 40℃; for 4h;Reflux;
(R)-2-methylpiperazine (1.25g, 12.5mmol), and K2CO3 (4.0g) were combined with chloroform (30 mL) in a 50mL flask fitted with a magnetic stirrer. A chloroform (25 mL) solution of 1-chloromethyl-4-vinylbenzene (4.00 g, 26.2 mmol) was added dropwise slowly within 30min at 40-50 °C under stirring. The reaction mixture was heated to reflux for 4h till the starting material disappeared by TLC detection (n-hexane:ethyl acetate=5:1, V/V). The resultant mixture was filtered to remove the solid. The solvent was removed from the filtrate under reduced pressure to yield a viscous oil that was then diluted with ethanol (60mL). Adding HCl/ethanol to the above solution till pH 1-2 yielded a white solid. The resultant precipitate was collected by suction filtration, washed with cold ethanol, and then mixed with water (10mL). The pasty was adjusted to pH 10-11 with ammonium hydroxide and then extracted with methylene dichloride twice (80 mL). The organic phase was washed with saturated brine and dried with magnesium sulfate. Removing solvent afforded 3.3 g (R)-MbVBP as white crystalline powders in 79.5percent yield based on (R)-2-methylpiperazine.
7-fluoro-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
[ 75336-86-6 ]
2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
In dimethyl sulfoxide; at 110℃;Sealed tube;
Example 12 2-(2-methylimidazo[l,2-b]pyridazin-6-yl)-7-[(3R)-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 (R)-2-methylpiperazine (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 (48 mg, 75%) as a light yellow solid. MS m/z 376.3 [M+H+].
75%
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 (R)-2-methylpiperazine (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 (48 mg, 75%) as a light yellow solid. MS m/z 376.3 [M+H+].
75%
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 (R)-2-methylpiperazine (68 mg, 0.677 mmol, 4.0 eq.) were stuffed in DMSO (2 mL) at 110C overnight. The solvent wasremoved 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 (48 mg, 75%) as a light yellow solid. MS m/z 376.3 [M+H?i.
75%
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 (R)-2-methylpiperazine (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 (48 mg, 75%) as a light yellow solid. MS m/z 376.3 [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 ]
[ 75336-86-6 ]
2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
In dimethyl sulfoxide; at 125℃;Sealed tube;
Example 25 2-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-9-methyl-7-[(3R)-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 (R)-2-methylpiperazine (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 (40 mg, 70%) as a light yellow solid. MS m/z 404.3 [M+H+].
70%
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 (R)-2-methylpiperazine (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 (40 mg, 70%) as a light yellow solid. MS m/z 404.3 [M+H+].
70%
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 (R)-2-methylpiperazine(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 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, 70%) as a light yellow solid. MS m/z 404.3 [M+Hi.
70%
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 (R)-2-methylpiperazine (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 (40 mg, 70%) as a light yellow solid. MS m/z 404.3 [M+H+].
3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-fluoro-2H-chromen-2-one hydrobromide[ No CAS ]
[ 75336-86-6 ]
3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 2h;
Step B: 3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-fluoro-2H-chromen-2-one hydrobromide (100 mg, 0.25 mmol) was stirred with (R)-2-methylpiperazine (52 mg, 0.52 mmol) in DMSO (0.5 mL) with K2CO3 (0.14 g, 1.0 mmol) at 120° C. for 2 h. The mixture was cooled to room temperature and diluted with water to produce a precipitate. The solid was collected by vacuum filtration and purified by silica gel chromatography (10percent MeOH in CH2Cl2) to give the title compound (64 mg, 64percent) as a yellow solid. MS m/z 390.2 [M+H]+; 1H NMR (500 MHz, CDCl3): delta 8.74 (1H, s), 8.45 (1H, s), 7.77 (1H, s), 7.51 (1H, d, J=8.8 Hz), 6.88 (1H, dd, J=8.8 Hz, 2.5 Hz), 6.77 (1H, d, J=2.5 Hz), 3.77-3.67 (2H, m), 3.21-3.14 (2H, m), 3.06-2.92 (3H, m), 2.91 (3H, s), 2.64-2.56 (1H, m), 2.48 (3H, s), 1.20 (3H, d, J=6.3 Hz).
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...
With sodium methylate; In methanol; at 25℃; for 1h;
Purified diastereomeric salt 41.3g (69mmol), dichloromethane 140ml, 35percent hydrochloric acid 25.0g (0.24mol), a mixture of distilled water 25ml to Kaishio, solid content was allowed to standfor liquid separation Upon dissolution. The resulting aqueous layer was concentrated to drynessto give (R) -2- methylpiperazine dihydrochloride 11.7 g. [Alpha] D: + 5.33 ° (C = 1.0 formic acid) (R)-2- methyl piperazine dihydrochloride 10.0g (58mmol) and 28percent sodium methoxide methanolsolution 23.2g the (0.12mol) was stirred for 1 hour free at 25 ° C. After filtering off theinsoluble matter, the solvent was evaporated. Residue to heating by the addition of cyclohexane30ml, after reflux, and the insoluble matter was filtered hot, and cooled to 20 ° C. The resultingcrystals isolated and dried to give (R)-2-methylpiperazine 4.5 g (60.0percent yield). [Alpha] D: -20.3 ° (C =1.0 t- butyl methyl ether), an optical purity of 99.6percent e. e. , Was a melting point of 90 ° C.
(R)-5-bromo-2-(3-methylpiperazin-1-yl)pyrimidine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With triethylamine; In ethanol; at 78℃; for 8h;Inert atmosphere;
EtOH (250 mL) was added to a mixture of 5-bromo-2-chloropyrimidine (5 g, 25.8 mmol) and (R)-2- methylpiperazine (2.74 g, 27.4 mmol) followed by the addition of TEA (9.98 mL, 71.6 mmol) under a nitrogen atmosphere. The reaction was stirred at about 78 °C for about 8 h. The reaction was cooled to about rt and concentrated under reduced pressure. The residue was triturated with 20: 1 DCM/MeOH (150 mL) and stirred for 30 min. The solid was collected by filtration and dried under vacuum to afford title compound (5 g, 75 percent) as the HC1 salt; lH NMR (400MHz, DMSO-t/6) delta 9.66 (br. s., 2H), 8.53 (s, 2H), 4.53 (d, J=13.7 Hz, 2H), 3.34 - 3.20 (m, 3H), 3.18 - 3.08 (m, 1H), 3.03 - 2.92 (m, 1H), 1.29 (d, J=6.2 Hz, 3H)
(R)-1-(5-fluoropyridin-2-yl)-3-methylpiperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
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 (R)-2-methylpiperazine (2 g, 20 mmol), 2-bromo-5-fluoro pyridine (3.72 g, 20 mmol), t-BuONa (3.844 g, 40 mmol), BINAP (1.245 g, 2 mmol), and Pd2(dba)3 (916 mg, 1 mmol) in dry toluene (20 mL) was stirred under N2 at 80 °C for 16 h. The reaction mixture was concentrated and purified by chromatography (silica, EtOAc/PE = 1/5) to afford (R)-1-(5- fluoropyridin-2-yl)-3-methylpiperazine (2.7 g, 13.8 mmol, 69percent) as a yellow oil. ESI-MS (EI, m/z): 196.1 [M+H]t
Multi-step reaction with 5 steps
1: dichloromethane / 1 h / 0 °C
2: pyridine / dichloromethane / 24 h / 0 - 20 °C
3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 24 h / 0 - 20 °C
4: hydrogenchloride; methanol / water; 1,4-dioxane / 12 h / 20 °C
5: formic acid / water / 3 h / 90 - 100 °C
Multi-step reaction with 6 steps
1: dichloromethane / 1 h / 0 °C
2: pyridine / dichloromethane / 24 h / 0 - 20 °C
3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 24 h / 0 - 20 °C
4: hydrogenchloride / 1,4-dioxane / 12 h / 20 °C
5: formic acid / water / 3 h / 95 °C
6: isopropyl alcohol / 3 h / Reflux
Multi-step reaction with 7 steps
1.1: dichloromethane / 1 h / 0 °C
2.1: pyridine / dichloromethane / 24 h / 0 - 20 °C
3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 24 h / 0 - 20 °C
4.1: hydrogenchloride; methanol / 1,4-dioxane / 12 h / 20 °C
5.1: formic acid / water / 3 h / 95 °C
6.1: N-ethyl-N,N-diisopropylamine / toluene / 0.5 h / 70 °C
6.2: 3 h / 95 °C
7.1: isopropyl alcohol / 3 h / Reflux
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