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N-ethyl-[[1-(2-pyrimidinyl)-4-piperidinyl]methyl]amine[ No CAS ]
[ 535-83-1 ]
N-Ethyl-N-[[1-(2-pyrimidinyl)-4-piperidinyl]methyl]formamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With sodium borohydrid; sodium carbonate In methanol; thionyl chloride; ethanol; N,N-dimethyl-formamide
20 N-Ethyl-N-[[1-(2-pyrimidinyl)-4-piperidinyl]methyl]formamide
EXAMPLE 20 N-Ethyl-N-[[1-(2-pyrimidinyl)-4-piperidinyl]methyl]formamide Trigonelline (3-carboxy-1-methylpyridinium hydroxide inner salt; 3.47 g, 20 mmole) was refluxed in thionyl chloride (17 ml) for 4 hr. The excess thionyl chloride was removed in vacuo and then DMF (50 ml) was added followed by N-ethyl-[[1-(2-pyrimidinyl)-4-piperidinyl]methyl]amine (see Example 17; 3.30 g, 15 mmole) and sodium carbonate (4.75 g, 45 mmole). The mixture was heated to 70° for 20 hr and was then filtered and concentrated in vacuo. The residue was dissolved in 95% ethanol (500 ml) and stirred with sodium borohydride (2.12 g, 56 mmole) and 0° for 4 hrs. The solution was warmed to room temperature and more sodium borohydride (2.0 g) was added. The solution was refluxed 18 hrs, cooled, quenched with acetone, and filtered. The solution was concentrated in vacuo and the residue was chromatographed on silica gel using 5% methanol/ethyl acetate as the eluent to give an off white powder (0.90 g, 18%). This material proved not to be the expected trigonelline product, but was instead the formamide product of formula I.
1-Methyl-3-[2-(9-guanylmethoxy)ethoxy]carbonyl}pyridinium iodide[ No CAS ]
[ 535-83-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
dmap; In pyridine;
To a solution of 1.0 g (4.4 mmol) of acyclovir in 25 mL of freshly distilled dry pyridine were added 2.27 g (4.4 mmol) of trigonelline anhydride diiodide and a catalytic amount (5.4 mg. 4 mmol) of 4-(dimethylamino)pyridine (DMAP). The resultant suspension was stirred for 4 days under argon at room temperature. As the reaction proceeded, the orange color of the anhydride was replaced with a yellow color. When all of the acyclovir had been consumed, the reaction was stopped, the precipitate (containing the product ester plus the trigonelline formed as a by-product) was removed by filtration and washed with acetone and ether to remove DMAP. The yellow solid was then stirred in dry methanol at room temperature to remove trigonelline, unreacted anhydride and acyclovir. The title compound was obtained in 87% yield (1.82 g), melting at 201-202 C. NMR and UV analyses confirmed that the product had the formula: STR132
87%
dmap; In pyridine;
To a solution of 1.0 g (4.4 mmol) of acyclovir in 25 mL of freshly distilled dry pyridine were added 2.27 g (4.4 mmol) of trigonelline anhydride diiodide and a catalytic amount (5.4 mg, 4 mmol) of 4-(dimethylamino)pyridine (DMAP). The resultant suspension was stirred for 4 days under argon at room temperature. As the reaction proceeded, the orange color of the anhydride was replaced with a yellow color. When all of the acyclovir had been consumed, the reaction was stopped, the precipitate (containing the product ester plus the trigonelline formed as a by-product) was removed by filtration and washed with acetone and ether to remove DMAP. The yellow solid was then stirred in dry methanol at room temperature to remove trigonelline, unreacted anhydride and acyclovir. The title compound was obtained in 87% yield (1.82 g), melting at 201-202 C. NMR and UV analyses confirmed that the product had the formula: STR131
87%
dmap; In pyridine;
To a solution of 1.0 g (4.4 mmol) of acyclovir in 25 mL of freshly distilled dry pyridine were added 2.27 g (4.4 mmol) of trigonelline anhydride diiodide and a catalytic amount (5.4 mg, 4 mmol) of 4-(dimethylamino)pyridine (DMAP). The resultant suspension was stirred for 4 days under argon at room temperature As the reaction proceeded, the orange color of the anhydride was replaced with a yellow color. When all of the acyclovir had been consumed, the reaction was stopped, the precipitate (containing the product ester plus the trigonelline formed as a by-product) was removed by filtration and washed with acetone and ether to remove DMAP. The yellow solid was then stirred in dry methanol at room temperature to remove trigonelline, unreacted anhydride and acyclovir. The title compound was obtained in 87% yield (1.82 g), melting at 201-202 C. NMR and UV analyses confirmed that the product had the formula: STR130
1
EXAMPLE 1The preparation of trigonelline thermolysateTrigonelline thermolysate was prepared by thermal degradation (pyrolysis) of trigonelline at 220° C. for 30 minutes. Trigonelline (in a form of a thin layer of crystals) was pyrolysed in a thin-wall glass ampoule filled with argon.The resulting mixture of the pyrolysis products was dissolved in water, the solution was filtered and extracted with chloroform. Water was distilled off using rotary evaporator and the residue was dried over phosphorus pentoxide.Preliminary analysis of the pyrolysis products (thermolysate) by means of the mass spectrometry technique ToF-SIMS (Time of Flight Secondary Ion Mass Spectrometry) is presented below.The major product of the pyrolysis is probably 1-methylpyridinium cation, which is predominant in the spectrum. Other products present in significant amounts are 1,2- and 1,4-dimethylpyridinium cations, and cations of: methyltrigonelline, (2'-hydroxypyridine)trigonelline, N-methyl(pyridine)-pyridinium and N-methyl(N'-methylpyridine)pyridinium.
The above material is redissolved in 250 ml of Ethyl alcohol, filtered through 41 Whatmann filter paper and cooled to 0 C. At that temperature a dry stream of Hydrogen chloride gas is passed through this to precipitate the Trigonelline hydrochloride. The precipitate was filtered out on filter paper and washed with cold ethyl alcohol and dried under vacuum at 60 C.; The above material is redissolved in 250 ml of Ethyl alcohol, filtered through 41 Whatmann filter paper and cooled to 0 C. A dry stream of Hydrogen chloride gas is passed through this to precipitate the Trigonelline hydrochloride. The precipitate was filtered out on filter paper and washed with cold ethyl alcohol and dried under vacuum at 60 C.The dried mass is redissolved in 150 ml of deionised water and filtered free of insoluble. The solution is concentrated under vacuum at 50 C. to a solid content of 20% and spray dried in a co-current indirect hot air spray dryer under following conditions.
2.1. Synthesis
General procedure: Trigonelline monohydrate was prepared according the method reported previously [30]. The complex of trigonelline, TRG, with squaric acid, H2SQ, was prepared by mixing solutions of 0.5 g of TGR in 1 mL of methanol and 0.4 g of H2SQ in 3 mL of water. The precipitate was filtered off. The crude product was recrystallized from a methanol-water mixture (1:1) to gave the crystals 1, m.p. 228 °C. When the solid obtained was recrystallized from water the crystals 2 were grown, m.p. 227 °C, while from 98% ethanol the crystals 3 were isolated, m.p. 225-226 °C.
2.1. Synthesis
General procedure: Trigonelline monohydrate was prepared according the method reported previously [30]. The complex of trigonelline, TRG, with squaric acid, H2SQ, was prepared by mixing solutions of 0.5 g of TGR in 1 mL of methanol and 0.4 g of H2SQ in 3 mL of water. The precipitate was filtered off. The crude product was recrystallized from a methanol-water mixture (1:1) to gave the crystals 1, m.p. 228 °C. When the solid obtained was recrystallized from water the crystals 2 were grown, m.p. 227 °C, while from 98% ethanol the crystals 3 were isolated, m.p. 225-226 °C.
2.1. Synthesis
General procedure: Trigonelline monohydrate was prepared according the method reported previously [30]. The complex of trigonelline, TRG, with squaric acid, H2SQ, was prepared by mixing solutions of 0.5 g of TGR in 1 mL of methanol and 0.4 g of H2SQ in 3 mL of water. The precipitate was filtered off. The crude product was recrystallized from a methanol-water mixture (1:1) to gave the crystals 1, m.p. 228 °C. When the solid obtained was recrystallized from water the crystals 2 were grown, m.p. 227 °C, while from 98% ethanol the crystals 3 were isolated, m.p. 225-226 °C.
trigonelline epigallocatechin gallate cocrystal[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water at 20℃; for 3.5h;
1 Example 1 Trigonelline Epigallocatechin gallate (EGCG) cocrystal (1 : 1)
500 mg (1.091 mmol) 92 % of ECGG was dissolved in 1.1 ml of water at ambient temperature. To this clear solution 169.21 mg (1.091 mmol) of Trigonelline hydrate was added and the slurry stirred for 3 hrs and 30 minutes. The obtained mass was filtered and dried under vacuum to give the title compound
2 Example 2 Trigonelline Chlorogenic acid cocrystal (1 : 1)
200 mg (1.29 mmol) of Trigonelline hydrate was dissolved in 1 ml of methanol at ambient temperature. To this clear solution 530 mg (1.46 mmol) of chlorogenic acid was added and the slurry was stirred for 1 hr and 30 minutes. The obtained mass was filtered and dried under vacuum to give the title compound.
3 Example 3 Trigonelline Quercetin Cocrystal (1 : 1)
155 mg (1 mmol) of Trigonelline hydrate was dissolved in 4 ml of methanol at ambient temperature. To this clear solution 338 mg (1 mmol) of Quercetin dihydrate was added and the slurry was stirred for 5 hrs. The resulting wet solid was filtered, dried under vacuum to give the title compound.
trigonelline (2S,3R,4S)-4-hydroxyisoleucine cocrystal[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water at 20℃; for 6h;
4 Example 4 Trigonelline 4-hydroxyisoleucine cocrystal (1 : 1)
330 mg (2.24 mmol) of 4-hydroxyisoleucine and 316.3 mg (2.04 mmol) Trigonelline hydrate were dissolved in 2.4 ml of water at ambient temperature. To this clear solution acetone (anti solvent) was added and the slurry stirred for 6 hrs. The resulting wet cake was filtered and dried under vacuum to give the title compound.
1 Example 1. Preparation of Epieatechin Trigonelline cocrystals
General procedure: Epieatechin : trigonelline is taken in mixture of ethanol: water sol vents and heated up to 55 °C- 58 °C until get a clear solution. Solution is kept at RT for 2-3 days to obtain desired co-crystal. Tire various parameters of the process to obtain co-crystals are listed below at Table 1. Different samples of epieatechin : trigonelline are analyzed as below.
1 Example 1. Preparation of Epieatechin Trigonelline cocrystals
General procedure: Epieatechin : trigonelline is taken in mixture of ethanol: water sol vents and heated up to 55 °C- 58 °C until get a clear solution. Solution is kept at RT for 2-3 days to obtain desired co-crystal. Tire various parameters of the process to obtain co-crystals are listed below at Table 1. Different samples of epieatechin : trigonelline are analyzed as below.
1 Example 1. Preparation of Epieatechin Trigonelline cocrystals
General procedure: Epieatechin : trigonelline is taken in mixture of ethanol: water sol vents and heated up to 55 °C- 58 °C until get a clear solution. Solution is kept at RT for 2-3 days to obtain desired co-crystal. Tire various parameters of the process to obtain co-crystals are listed below at Table 1. Different samples of epieatechin : trigonelline are analyzed as below.
Stage #1: pyridine-3-carboxylic acid With dimethyl sulfate at 25 - 133℃; for 4.16667h;
Stage #2: With sulfuric acid In lithium hydroxide monohydrate; isopropanol at -5 - 70℃; for 2.16667h;
COMPARATIVE EXAMPLE
Nicotinic acid (50 gms, 0.40 moles) and dimethyl sulfate (77 gms, 0.61 moles) were added into round bottom flask and stirred the contents for 10 min at 25-35 °C. The reaction mass was slowly heated to reflux (127-133°C) and maintained for 4 hrs for reaction completion (compound Illa impurity content: 20-30%). The reaction mass was allowed to cool to 25-35°C, added DM water (400 ml) and stirred for 10 min. Sulfuric acid (2 ml) was slowly added into reaction mass at 25-35°C and concentrated the reaction mass completely below 70°C under vacuum. Isopropanol (50 ml) was added to the reaction mass and co-distilled under reduced pressure below 70°C. Isopropanol (350 ml) was added to the reaction mass at 55-65°C and stirred for 10 min. The reaction mass was allowed to Cool to -5°C to 5°C and stirred for 2 hrs. Filtered the solids, washed with isopropanol (50 ml) and suck dried the wet solid for 30 min. DM water (150 ml) was added to the wet solid and stirred for 15 min and cooled the contents to -5°C to 5°C, pH adjusted to 7.0-7.5 with 10% w/v sodium hydroxide solution and stirred for 15 min. The reaction mass was distilled at 70°C under vacuum followed by co-distilling with methanol (50 ml). Methanol (400 ml) was added, heated to 60-65°C and stirred for 30min. The reaction mass was allowed to cool to 25-35°C, filtered the salts and washed with methanol (50 ml). Distilled the filtrate at 60°C under vacuum, added isopropanol (250 ml), heated to 60-65°C and stirred for 15 min. Cooled the reaction mass to -5°C to 5°C, stirred for 2 hrs, filtered the solids and washed with cold isopropanol (50 ml). The wet solid was dried in vacuum oven at 40-45°C for 6-8 hrs to get 25 gms of trigonelline. HPLC Purity: 99.5%.
1
DM water (500 ml) and sulfuric acid (20 ml) were added to compound of formula III obtained above. The reaction mass was heated to 85-95°C and stirred for 6-8hrs at the same temperature. The reaction mass was allowed to cool to 60°C and distilled out water completely under vacuum at below 70°C. Isopropanol (100 ml) was added to the reaction mass at 45-55°C, co-distilled under reduced pressure below 70°C, degassed. Isopropanol (700 ml) was added to the reaction mass, heated to 65-75°C and stirred for 60-90mins. The reaction mass was allowed to cool to 25-35°C and stirred for 60-90 mins. Filtered the solids, washed with isopropanol (100 ml) and suck dried the wet solid. DM water (300 ml) was added to the wet solid and stirred for 10-15 min at 25-35°C. The reaction mass pH was adjusted to 6.0-6.5 with 10% sodium hydroxide solution. The reaction mass was distilled at below 70°C under vacuum followed by co-distilled with isopropanol (100 ml) under reduced pressure below 70°C. Methanol (100 ml) was added to the reaction mass and was distilled at below 60°C under vacuum and degassed for Ihr. Methanol (500 ml) was added at 35-45°C, allowed to cooled to 15- 25°C and stirred for 30 mins at 15-25°C. Filtered the solids, washed with methanol (50 ml) and distilled the filtrate below 60°C under vacuum. The reaction mass was cooled to 45-55 °C, added isopropanol (100 ml) and co-distilled at below 60°C under vacuum. Added isopropanol (700 ml) at 35-45°C, heated to 65-75°C and stirred for 60-90 mins. Cooled the mass to 25-35°C, stirred for 60-90mins, filtered the solids and washed with isopropanol (100 ml). Dry the wet solid in vacuum oven at 25-35°C for 1-2 hrs and at 50-60°C for 8-12 hrs to get 94.4 gms of trigonelline. HPLC Purity: 99.5%; content of nicotinic acid of formula II: 0.01%. Residual solvents: Methanol: 211 ppm; Isopropanol: 498 ppm.
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