2-hydroxyethyl(trimethyl)azanium;hydroxide

反応条件: temp:64.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 250 mL three-necked round-bottomed flask was charged with {(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid (20.0 g, 42.2 mol) and methanol (150 mL), under nitrogen. To the resulting slurry was then added 45% by wt. of choline hydroxide in methanol (12.8 mL, 45.3 mol), in one portion. Shortly after the addition, a homogeneous clear solution was obtained. The solution was aged at room temperature for about 1 hour, then clarified by filtration through a medium sintered glass filter. The resulting filtered solution was concentrated by distillation (at a temperature of about 63-65° C.) to a residual volume of about 55-60 mL. While at the elevated temperature, EtOAc (140-150 mL) was added by an addition funnel over a period of about 40 minutes, while maintaining a temperature of about 63-65° C. The resulting clear solution was seeded, then cooled slowly under moderate agitation to ambient temperature. The resulting slurry was then aged overnight, cooled to about 5-10° C. and aged at this temperature for about 2 hours. The resulting solid was collected by filtration, rinsed with cold EtOAc (40 mL, 2C) and dried in a vacuum oven at 50° C., overnight to yield the title compound as a white crystalline solid. Shortly after the addition a homogeneous clear solution was obtained clarified by filtration through a medium sintered glass filter The resulting filtered solution was concentrated by distillation (at a temperature of about 63-65° C.) to a residual volume of about 55-60 mL While at the elevated temperature, EtOAc (140-150 mL) was added by an addition funnel over a period of about 40 minutes cooled slowly under moderate agitation to ambient temperature The resulting slurry was then aged overnight cooled to about 5-10° C. aged at this temperature for about 2 hours The resulting solid was collected by filtration rinsed with cold EtOAc (40 mL, 2C) dried in a vacuum oven at 50° C., overnight

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 30.2 g of 5,8,11,14,17-cis-eicosapentaenoic acid (EPA, purity >90%) are treated with 12.1 of choline hydroxide according to one of the procedures described in examples 1 to 3. After charcoal treatment EPA choline salt is thus obtained with a nearly theoretical yield. The product is water-soiuble and its physicochemical and analytical characteristics conform to the expected values.

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7-Chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (1.00 g, 2.61 mM) was stirred in methanesulfonic acid (10 mL) to give a brown solution. This solution was heated to 150° C. for 3 hours and cooled to room temperature. The cooled solution was added dropwise to water (50 mL) with stirring to give a grey suspension which was stirred for 20 hours and filtered. The collected solids were washed with water and then suspended in water (50 mL). To this suspension was added choline hydroxide solution (2 mL, 45 wt % in methanol) which dissolved the solids to give a brown solution. This solution was heated to reflux for 1 hour, additional choline hydroxide solution (2 mL) was added and the solution was heated to reflux for 3 hours. The solution was cooled to room temperature and acidified to pH=1 with 1N HCl to give a brown suspension. The suspension was filtered and the collected solids were washed with water to give a brown solid. Several recrystallizations from hot methanol gave the title compound as an off-white powder (0.35 g, 36%), mp 287° C. (decomp.); MS(CI): 370. to give a brown solution cooled to room temperature to give a grey suspension which was stirred for 20 hours filtered The collected solids were washed with water To this suspension was added choline hydroxide solution (2 mL, 45 wt % in methanol) which dissolved the solids to give a brown solution This solution was heated to reflux for 1 hour the solution was heated to reflux for 3 hours The solution was cooled to room temperature to give a brown suspension The suspension was filtered the collected solids were washed with water to give a brown solid Several recrystallizations from hot methanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred suspension of 7-chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (400 mg, 1.03 mM) in methanol (4 mL) was added choline hydroxide (45% by weight in methanol, 295.6 μL, 1.03 mM). After brief sonication, all solids dissolved and the resulting solution was filtered through a Gelman Glass Acrodisc filter (0.45 μm) along with an additional quantity of methanol (8 mL). The filtrate was concentrated to dryness and the residual oil was stirred with isopropanol (15 mL) and ethanol (8 mL) whereupon crystallization occurred. The solids were collected and dried under vacuum at 100° C. overnight to give the title compound (411 mg, 81 %) as a yellow solid, mp 229-230° C. After brief sonication all solids dissolved the resulting solution was filtered through a Gelman Glass Acrodisc filter (0.45 μm) along with an additional quantity of methanol (8 mL) The filtrate was concentrated to dryness The solids were collected dried under vacuum at 100° C. overnight

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (Z)-5-(2-hydroxy-3-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) was dissolved in 5 mL of tetrahydrofuran to form a dark red suspension. The reaction mixture was added with 45% solution of choline hydroxide in methanol (45 mg, 0.44 mmol) to form a purple solution, and stirred for 1 hour at room temperature. The solid was precipitated from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 mL×3) and dired in vacuo to obtain the title compound (Z)-5-(2-hydroxy-3-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(choline) 8 (140 mg, yield: 96.6%) as a dark red solid. to form a dark red suspension to form a purple solution The solid was precipitated from solution filtered the filter cake was washed with tetrahydrofuran (1 mL×3) and dired in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: From Choline Chloride and Choline Hydroxide. A 10% choline buffer was prepared from equal portions of 10% choline chloride and 10% choline hydroxide. The 10% choline chloride solution was prepared from 10 g of choline chloride diluted to 100 ml with water. The 10% choline hydroxide solution was prepared by diluting a 50% solution, decolorizing with charcoal, and filtering. Choline hydroxide may also be prepared from choline chloride by ion exchange chromatography. filtering Choline hydroxide may also be prepared from choline chloride by ion exchange chromatography

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12-L reaction flash was charged with 2.0 kg diazoxide and 5.0-L THF with stirring and heating to 55° C. Choline hydroxide (45% solution in methanol, 2.32 L) was added dropwise to this reaction mixture over about 2.5 hr with stirring. The temperature was maintained at 60±5° C. After addition of choline hydroxide, stirring was continued for about 30 min. The reaction mixture was clarified by in-line 10 micron filtration upon transfer to a 22-L reaction flask pre-charged with 2-L pre-filtered THF, into which was added 10-L pre-filtered MTBE dropwise. This reaction mixture was transferred to another flask which was then charged with an additional 30-L pre-filtered MTBE dropwise, with adjustment of temperature to <5° C. and stirring for about 2 hr. Diazoxide choline salt was recovered by vacuum filtration to afford 2.724 kg (94%) diazoxide choline salt (99.8%, HPLC purity), confirmed by 1H NMR, IR, and UV/Visible analysis. with stirring The temperature was maintained at 60±5° C stirring The reaction mixture was clarified by in-line 10 micron filtration upon transfer to a 22-L reaction flask pre-charged with 2-L pre-filtered THF into which was added 10-L pre-filtered MTBE dropwise This reaction mixture was transferred to another flask which was then charged with an additional 30-L pre-filtered MTBE dropwise with adjustment of temperature to <5° C. and stirring for about 2 hr Diazoxide choline salt was recovered by vacuum filtration

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 400 mg (0.63 mmol) of 1-[6-fluoro-8-methoxy-3-({[2-methyl-4-(trifluoromethoxy)benzyl]amino}carbonyl)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylic acid (Example 47) are suspended in 20 ml of deionized water and 20 ml of acetonitrile at RT. 140 μl (153 mg, 0.63 mmol) of β-hydroxyethyltrimethylammonium hydroxide (“choline hydroxide”) are added and the mixture is stirred at RT overnight. The resulting solution is freed from the acetonitrile on a rotary evaporator. The aqueous solution which remains was frozen and lyophilized. 494 mg (100% of theory) of residue, which is found by analysis to correspond to the title compound, are obtained. at RT The resulting solution is freed from the acetonitrile on a rotary evaporator The aqueous solution which remains was frozen are obtained

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Hemisuccinate [5] (1.0173 g, 4 mmol) was dissolved in 10 ml of methanol and chilled to 0° C. Choline hydroxide in (1.13 ml, 40% sol. in methanol, 4 mmol) was added dropwise and the reaction mixture was stirred for 5 min at 0° C. The solvent was evaporated and remaining volatile material was removed under reduced pressure (0.01 mbar) to yield product [6] as yellow liquid in quantitative yield. The product was pure according to 1H NMR without further purification. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=5.28 (t, J=7.0 Hz, 1H), 5.07 (t, J=6.8 Hz, 1H), 4.49 (d, J=7.0 Hz, 2H), 3.85 (m, 2H), 3.44 (m, 2H), 3.13 (s, 9H), 2.36 (t, J=7.2 Hz, 2H), 2.10 (t, J=7.2 Hz, 2H), 2.03 (m, 4H, 1.65 (s, 6H), 1.57 (s, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=174.0, 173.6, 140.7, 131.1, 123.8, 119.0, 67.3, 60.2, 55.0, 53.1, 39.3, 32.8, 31.2, 25.8, 25.5, 17.6, 16.2. Tg−65° C., T5%onset 170° C. The solvent was evaporated was removed under reduced pressure (0.01 mbar)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Hemisuccinate [5] (1.0173 g, 4 mmol) was dissolved in 10 ml of methanol and chilled to 0° C. Choline hydroxide in (1.13 ml, 40% sol. in methanol, 4 mmol) was added dropwise and the reaction mixture was stirred for 5 min at 0° C. The solvent was evaporated and remaining volatile material was removed under reduced pressure (0.01 mbar) to yield product [6] as yellow liquid in quantitative yield. The product was pure according to 1H NMR without further purification. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=5.28 (t, J=7.0 Hz, 1H), 5.07 (t, J=6.8 Hz, 1H), 4.49 (d, J=7.0 Hz, 2H), 3.85 (m, 2H), 3.44 (m, 2H), 3.13 (s, 9H), 2.36 (t, J=7.2 Hz, 2H), 2.10 (t, J=7.2 Hz, 2H), 2.03 (m, 4H, 1.65 (s, 6H), 1.57 (s, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=174.0, 173.6, 140.7, 131.1, 123.8, 119.0, 67.3, 60.2, 55.0, 53.1, 39.3, 32.8, 31.2, 25.8, 25.5, 17.6, 16.2. Tg−65° C., T5%onset 170° C. The solvent was evaporated was removed under reduced pressure (0.01 mbar)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Salicylic acid (5 or 10 mmol) and choline hydroxide (5 mmol, 40% solution in MeOH) were dissolved in 20 ml of methanol and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. The solvent was evaporated the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Salicylic acid (5 or 10 mmol) and choline hydroxide (5 mmol, 40% solution in MeOH) were dissolved in 20 ml of methanol and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. The solvent was evaporated the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs