(R)-(-)-2-Methylpiperazine

white to light yellow crystalline powder

(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.]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 (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 to Example 1. Was the first crystallizationfrom ( '1 crystallization' was described as) (described as crystallization) last crystallization upto six steps. Compared to the Comparative 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 (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.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.

The new chiral group is widely used in the synthesis of chiral drugs.

Valuable synthon for quinoline antibacterials.