* 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 potassium hydroxide In methanol; water at 20℃; for 31 h;
Example 1 - Preparation of crude Moxonidine by an improved process, as described in a copending application A mixture of 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-amino-pyrimidine (5 g, 0.0174 mol) and 85percent potassium hydroxide powder (1.276 g, 0.019 mol, 1.1 equiv.) in methanol (40 ml) was stirred at ambient temperature for 30 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 * 10 ml) and 2-propanol (3 * 10 ml) and dried at 50° C overnight to give 3.5 g of crude Moxonidine in 83.5percent yield, having a purity of 98.2percent (by HPLC).
Reference：
[1] Patent: EP1894926, 2008, A1, . Location in patent: Page/Page column 7
[2] Patent: US4323570, 1982, A,
[3] Patent: US4323570, 1982, A,
2
[ 67-56-1 ]
[ 75438-54-9 ]
[ 352457-35-3 ]
[ 75439-01-9 ]
[ 75438-57-2 ]
Yield
Reaction Conditions
Operation in experiment
88.3%
With sodium hydrogencarbonate In water at 65℃; for 6 h;
The same reaction, which is provided in example 17, was carried out using sodium bicarbonate powder in methanol, optionally with addition of small volume of water (example 29), at different reaction conditions, as depicted in Table 6.
88.3%
With potassium hydrogencarbonate In water at 65℃; for 10 h;
The same reaction, which is provided in example 17, was carried out using potassium bicarbonate powder in methanol, optionally with addition of small volume of water (example 31), at different reaction conditions, as depicted in Table 7.
85.9%
at 20℃; for 16 h;
Example 32 - Preparation of Moxonidine by reaction of DMAIA with a mixture of aqueous potassium hydroxide and solid potassium carbonate at ambient temperature A mixture of DMAIA (5 g, 0.0174 mol) and 45percent potassium hydroxide solution (0.023 mol, 1.3 equiv.) and solid potassium carbonate (0.004 mol, 0.2 equiv.) in methanol (40 ml) was stirred at ambient temperature for 16 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to yield 3.6 g of crude Moxonidine in 85.9percent yield, having a purity of 99.07percent (by HPLC), containing 0.03percent of impurity (III) and 0.90percent of impurity (IV).
85.9%
at 65℃; for 9 h;
The same reaction, which is provided in example 17, was carried out using potassium bicarbonate powder in methanol, optionally with addition of small volume of water (example 31), at different reaction conditions, as depicted in Table 7.
83.5%
at 20 - 25℃; for 24 - 30 h;
Example 17 - Preparation of Moxonidine by reaction of DMAIA with 1.3 equivalents of 85percent potassium hydroxide powder at ambient temperature A mixture of DMAIA (5 g, 0.0174 mol) and 85percent potassium hydroxide powder (1.5 g, 0.0226 mol, 1.3 equiv.) in methanol (40 ml) was stirred at ambient temperature for 24 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to give 3.7 g of crude Moxonidine in 88.3percent yield, having a purity of 99.49percent (by HPLC), containing 0.01percent of impurity (III) and 0.50percent of impurity (IV). The same reaction, which is provided in example 17, was carried out using 85percent potassium hydroxide powder in methanol at different reaction conditions, as depicted in Table 4.
81.1%
at 45 - 65℃; for 4 - 18 h;
Example 10 - Preparation of Moxonidine by reaction of DMAIA with 1.0 molar equivalent of potassium carbonate A mixture of DMAIA (5 g, 0.0174 mol) and potassium carbonate (2.4 g, 0.0174 mol, 1.0 molar equiv.) in methanol (40 ml) was heated at 45-50° C for 18 hours. Then, the reaction mixture was cooled to ambient temperature and acetic acid (4 ml) and water (35 ml) were added. After stirring for half an hour, 25percent solution of ammonium hydroxide (4 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water and dried at 50° C overnight to give 3.8 g of crude Moxonidine in 90.7percent yield, having a purity of 99.23percent (by HPLC), containing 0.10percent of impurity (III) and 0.67percent of impurity (IV). The same reaction, which is provided in example 10, was carried out using potassium carbonate in methanol at different reaction conditions, as depicted in Table 2.
81.1%
With potassium hydroxide In water at 20 - 65℃; for 2 - 11 h;
Example 20 - Preparation of Moxonidine by reaction of DMAIA with 45percent aqueous potassium hydroxide solution at ambient temperature A mixture of DMAIA (5 g, 0.0174 mol) and 45percent aqueous potassium hydroxide solution (1.8 g, 0.029 mol, 1.7 equiv.) in methanol (40 ml) was stirred at ambient temperature for 10 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to give 3.7 g of crude Moxonidine in 88.3percent yield, having a purity of 99.45percent (by HPLC), containing 0.03percent of impurity (III) and 0.52percent of impurity (IV). The same reaction, which is provided in example 20, was carried out using aqueous potassium hydroxide in methanol at different reaction conditions, as depicted in Table 5.
81.1%
With sodium hydroxide In water at 40 - 65℃; for 2 - 10 h;
Example 13 - Preparation of Moxonidine by reaction of DMAIA with 1.5 equivalents of 47percent aqueous solution of sodium hydroxide A mixture of DMAIA (5 g, 0.0174 mol) and 47percent aqueous solution of sodium hydroxide (1.25 g, 0.026 mol, 1.5 equiv.) in methanol (40 ml) was stirred at 40-50° C for 10 hours. Then, the reaction mixture was cooled to ambient temperature and water (50 ml) was added. After stirring for one hour, a colorless precipitate was collected by filtration, washed with water (3 *10 ml) and 2-propanol (3 *10 ml) and dried at 50° C overnight to yield 3.7 g of crude Moxonidine in 88.3percent yield, having a purity of 99.52percent (by HPLC), containing 0.04percent of impurity (III) and 0.44percent of impurity (IV). The same reaction, which is provided in example 13, was carried out using sodium hydroxide solution in methanol at different reaction conditions, as depicted in Table 3.
71.1%
at 40 - 65℃; for 14.5 - 24 h;
The same reaction, which is provided in example 17, was carried out using sodium bicarbonate powder in methanol, optionally with addition of small volume of water (example 29), at different reaction conditions, as depicted in Table 6.
The same reaction, which is provided in example 13, was carried out using sodium hydroxide solution in methanol at different reaction conditions, as depicted in Table 3.
88.3%
at 25℃; for 12 h;
The same reaction, which is provided in example 17, was carried out using 85percent potassium hydroxide powder in methanol at different reaction conditions, as depicted in Table 4.
Example 1 - Preparation of Moxonidine by reaction of DMAIA with 1.1 equivalents of sodium methoxide at ambient temperature Sodium methoxide (25percent solution in methanol, 7.7 ml, 0.0382 mol, 1.1 equiv.) was added at ambient temperature to a suspension of DMAIA (10 g, 0.0347 mol) in methanol (50 ml) and the reaction mixture was stirred at ambient temperature for 24 hours. Then, water (100 ml) was added and the reaction mixture was cooled to ambient temperature. A colorless product was collected by filtration, washed with water (3 *10 ml) and 2-propanol (3 *10 ml) and dried at 50° C overnight to give 7.4 g of crude Moxonidine in 88.3percent yield, having a purity of 99.17percent (by HPLC), containing 0.04percent of impurity (III) and 0.71percent of impurity (IV). The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
76.4%
at 25℃; for 30 h;
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
66.8%
at 25℃; for 30 h;
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
EXAMPLE [0057] Moxinidine was synthesized from DMAIA according to the following procedure. [0058] A 4 L glass reactor (with heating jacket) equipped with overhead stirrer, reflux condenser and internal thermometer was charged with DMAIA (149 g, 517 mmol) and activated charcoal (7.50 g). Methanol (3.45 L) and DBU (110 g, 722 mmol, 1.4 eq.) was added and the addition jar rinsed with methanol (100 mL). The jar containing DMAIA was rinsed with methanol (200 mL). The stirrer was turned on and the mixture was heated to reflux (65° C.) for 3.5 h. Then, acetic acid (14.1 g, 234 mmol, 0.45 eq) was added over 7 min. After vacuum filtration of the hot reaction mixture over a paper filter (MN 85/220) and rinsing of the filter cake with hot methanol (100 mL), the filtrate was transferred to a second reactor equipped with overhead stirrer, distillation head with condenser and internal thermometer. The temperature was set to 40-43° C. IT and seeding crystals (1.5 g) were added. A thin suspension formed while the suspension was stirred for 45 min. After further cooling to 20° C. within 1.5 h, the process was discontinued overnight. Then the mixture was concentrated by distillation in vacuo (290 mbar, ET 65° C., IT 37-38° C., dist. temp. 35-37° C., 4.25 h). 2.4 L of solvent were removed. The mixture was cooled to 4° C. within 3 h under stirring and kept at 0-5° C. for 1 h (vacuum was broken at an ET below 36° C.). The suspension was vacuum-filtered (on G4 filter frit) and the reactor rinsed with 450 mL of mother liquor (to collect the remaining product) and the filter cake (product) subsequently washed with cold methanol (120 mL), cold water (2×150 mL) and cold methanol (2×120 mL) to afford a colourless crystalline powder after drying at 60° C. for 19 h (overnight). yield: 106.2 g, 439 mmol, 84.4percent. Assay (HPLC): 99.5percent, Impurity A<0.05percent, impurity B 0.18percent, sulphated ash: 0.02percent.
83.5%
at 20℃; for 30 h;
Example 1 - Preparation of crude Moxonidine by an improved process, as described in a copending application A mixture of DMAIA (5 g, 0.0174 mol) and 85percent potassium hydroxide powder (1.276 g, 0.019 mol, 1.1 equiv.) in methanol (40 ml) was stirred at ambient temperature for 30 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to give 3.5 g of crude Moxonidine in 83.5percent yield, having a purity of 98.2percent (by HPLC).
3.43 g
With tetrabutylammomium bromide; water; sodium hydroxide In dichloromethane at 20 - 35℃; for 2.5 h;
Sodium hydroxide (10 ml, 50 percent aqueous solution, 5.0 g, 0.125 mol) was added to a solution of DMAIA (5.0 g, 0.0174 mol, 87 percent purity) in methanol (20 ml), methylene chloride (100 ml) and tetra-n-butylammonium bromide (0.32 g, 0.1 mol percent). The reaction was slightly exothermic and for a quarter of an hour the temperature reached 30 °C. Then the solution was heated at 35 °C for 2 hours. The aqueous phase was separated by funnel and the solvents from the organic phase were distillated. The residue was suspended in water (50 ml) and the precipitate was collected by filtration, washed with water till pH ~7 of the washing water and dried at 50 °C. The yield of Moxonidine was 3.43 g (93.97percent; toward 87percent of DMAIA purity) with a purity of 99.91 percent.
The same reaction, which is provided in example 10, was carried out using potassium carbonate in methanol at different reaction conditions, as depicted in Table 2.
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
Methanol (18000 ml) was added to 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)aminopyrimidine (600 gm) at room temperature and then heated to 30 to 35°C. To the reaction mass was added sodium methoxide (600 gm) slowly for 45 minutes. The solvent was distilled under vacuum below 30°C to obtain a residual solid and then added water (5500 ml). The reaction mass was stirred for 10 minutes and filtered. The solid thus obtained was dried to get 520 gm of moxonidine.Chromatographic purity of moxonidine: 99.78percent;Content of 6-chloromoxonidine: 0.03percent;Content of 4-methoxymoxonidine: 0.15percent.
EXAMPLE 4[0054] This example describes the preparation of moxonidine from DMAIA containing 5.7percent of iso-DMAIA.[0055] A mixture of DMAIA (5.0 g), iso-DMAIA (0.3 g), methanol (25 ml) and 25percent sodium methoxide solution in methanol (3.9 mi, 1.1 equiv.) was stirred at ambient temperature overnight. A sample of the reaction mixture was withdrawn and analyzed by HPLC indicating that the reaction mixture contained 87.9percent of moxonidine and 9.7percent of compound (VI). Water (50 ml) was then added to the reaction mixture and stirring was maintained at ambient temperature for 4 hours. A precipitate was collected by filtration, washed with water and 2-propanol and dried at 60° C overnight to yield 3.9 g of crude <n="16"/>Moxoπidine in 73.6percent yield, having a purity of 96.66percent and containing 0.12percent of the impurity VI (by HPLC).
COMPARATIVE EXAMPLE 1[0041] This example describes the preparation and purification of moxonidine as described in the '570 patent.[0042] 4,6~dicHoro-2-methyl-5-(l-acetyl-2-imidazoHn-2-yl)-aminopyrimidine (10 g) was mixed with a solution of sodium methoxide (NaOCHs) (3.78 g) in methanol (35 ml) and xefluxed for 2 hours. A sample was withdrawn, diluted with the HPLC eluent mixture and injected to the HPLC system. The sample contained 93.25percent of moxonidine, 1.48percent of 4,6- dichloro-2-niethyl-5-(2-imidazolin-2-yl)-aminopyrimidine (compound VII) and 5.27percent of 4,6- dimethoxy-2-methyl-(2-imidazolin-2-yl)-aminopyrimidine (compound VIII). Then, water (100 ml) was added, and the mixture was cooled and vacuum dried. A sample of the thus obtained solid was taken, dissolved in the HPLC eluent mixture and injected to the HPLC system. The sample contained 93.22percent of moxonidine, 1.45percent of 4,6-dichloro-2-metliyl-5-(2- imidazolin-2-yl)-aminopyrimidine and 5.32percent of 4,6-dimethoxy-2-methyl-(2-imidazolin-2- yl)-aminopyrimidine. The solid was heated under reflux in nitromethane (250 ml) for half an hour and the hot mixture was filtered. The filtrate was kept at 5°C overnight. A colorless precipitate was collected by filtration, washed with ethyl acetate and dried at 600C overnight to yeld 7.1 g of moxonidine having 93.44percent purity by HPLC and containing 1.19percent of 4,6- dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine and 5.37percent of 456-dimethoxy-2~ methyl-(2-imidazolin-2-yl)-aminopyrimidine.
1; 2; 3; 4; 6
Example 1 - Preparation of Moxonidine by reaction of DMAIA with 1.1 equivalents of sodium methoxide at ambient temperature Sodium methoxide (25% solution in methanol, 7.7 ml, 0.0382 mol, 1.1 equiv.) was added at ambient temperature to a suspension of DMAIA (10 g, 0.0347 mol) in methanol (50 ml) and the reaction mixture was stirred at ambient temperature for 24 hours. Then, water (100 ml) was added and the reaction mixture was cooled to ambient temperature. A colorless product was collected by filtration, washed with water (3 *10 ml) and 2-propanol (3 *10 ml) and dried at 50° C overnight to give 7.4 g of crude Moxonidine in 88.3% yield, having a purity of 99.17% (by HPLC), containing 0.04% of impurity (III) and 0.71% of impurity (IV). The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
76.4%
In tetrahydrofuran at 25℃; for 30h;
7
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
66.8%
In toluene at 25℃; for 30h;
8
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
In methanol for 2h; Heating / reflux;
1 Reference Example 1
Reference Example 1 - Preparation of Moxonidine by reaction of 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (DMAIA) with 2.02 equivalents of sodium methoxide at boiling temperature 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (10 g, 0.0347 mol) was mixed with a solution of sodium methoxide (3.78 g, 0.07 mol, 2.02 equiv.) in 35 ml of methanol and boiled for 2 hours. Then, water (100 ml) was added and the reaction mixture was cooled to ambient temperature. A colorless product was collected by filtration, washed with water and dried at 50° C overnight to yield crude Moxonidine containing 6.5% of impurity (III) and 0.61 % of impurity (IV).
Stage #1: 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine; sodium methylate In methanol for 2h; Heating / reflux;
Stage #2: With water In methanol
1 Reference Example 1
Reference Example 1 - Preparation of Moxonidine by reaction of 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (DMAIA) with 2.02 equivalents of sodium methoxide at boiling temperature 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazol in-2-yl)-aminopyrimidine, (DMAIA), (10 g, 0.0347 mol) was mixed with a solution of sodium methoxide (3.78 g, 0.07 mol, 2.02 equiv.) in 35 ml of methanol and boiled for 2 hours. Then, water (100 ml) was added and the reaction mixture was cooled to ambient temperature. A colorless product was collected by filtration, washed with water and dried at 50° C overnight to yield crude Moxonidine containing 6.5% of impurity (II) and 0.61 % of impurity (III).
In methanol; water at 20℃;
1
Reference Example 1 - Preparation of Moxonidine by reaction of 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (DMAIA) with sodium methoxide according to the teaching of the '570 patent. 4,6-dichloro-2-methyl-5-(-acetyl -2 -imidazolin-2 -yl)-aminopyrimi dine, (DMAIA), (10 g, 0.0347 mol) was mixed with a solution of sodium methoxide (3.78 g, 0.07 mol, 2.02 equiv.) in 35 ml of methanol and boiled for 2 hours. Then, water (100 ml) was added and the reaction mixture was cooled to ambient temperature. A colorless product was collected by filtration, washed with water and dried at 50° C overnight to yield crude Moxonidine [containing 6.5% of impurity II and 0.61% of impurity III].
With sodium hydrogencarbonate In water at 65℃; for 6h;
29
The same reaction, which is provided in example 17, was carried out using sodium bicarbonate powder in methanol, optionally with addition of small volume of water (example 29), at different reaction conditions, as depicted in Table 6.
88.3%
With potassium hydrogencarbonate In water at 65℃; for 10h;
31
The same reaction, which is provided in example 17, was carried out using potassium bicarbonate powder in methanol, optionally with addition of small volume of water (example 31), at different reaction conditions, as depicted in Table 7.
85.9%
With potassium hydroxide; potassium carbonate at 20℃; for 16h;
32 Example 32
Example 32 - Preparation of Moxonidine by reaction of DMAIA with a mixture of aqueous potassium hydroxide and solid potassium carbonate at ambient temperature A mixture of DMAIA (5 g, 0.0174 mol) and 45% potassium hydroxide solution (0.023 mol, 1.3 equiv.) and solid potassium carbonate (0.004 mol, 0.2 equiv.) in methanol (40 ml) was stirred at ambient temperature for 16 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to yield 3.6 g of crude Moxonidine in 85.9% yield, having a purity of 99.07% (by HPLC), containing 0.03% of impurity (III) and 0.90% of impurity (IV).
85.9%
With potassium hydrogencarbonate at 65℃; for 9h;
30
The same reaction, which is provided in example 17, was carried out using potassium bicarbonate powder in methanol, optionally with addition of small volume of water (example 31), at different reaction conditions, as depicted in Table 7.
83.5%
With potassium hydroxide at 20 - 25℃; for 24 - 30h;
17; 18
Example 17 - Preparation of Moxonidine by reaction of DMAIA with 1.3 equivalents of 85% potassium hydroxide powder at ambient temperature A mixture of DMAIA (5 g, 0.0174 mol) and 85% potassium hydroxide powder (1.5 g, 0.0226 mol, 1.3 equiv.) in methanol (40 ml) was stirred at ambient temperature for 24 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to give 3.7 g of crude Moxonidine in 88.3% yield, having a purity of 99.49% (by HPLC), containing 0.01% of impurity (III) and 0.50% of impurity (IV). The same reaction, which is provided in example 17, was carried out using 85% potassium hydroxide powder in methanol at different reaction conditions, as depicted in Table 4.
81.1%
With potassium carbonate at 45 - 65℃; for 4 - 18h;
10; 12
Example 10 - Preparation of Moxonidine by reaction of DMAIA with 1.0 molar equivalent of potassium carbonate A mixture of DMAIA (5 g, 0.0174 mol) and potassium carbonate (2.4 g, 0.0174 mol, 1.0 molar equiv.) in methanol (40 ml) was heated at 45-50° C for 18 hours. Then, the reaction mixture was cooled to ambient temperature and acetic acid (4 ml) and water (35 ml) were added. After stirring for half an hour, 25% solution of ammonium hydroxide (4 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water and dried at 50° C overnight to give 3.8 g of crude Moxonidine in 90.7% yield, having a purity of 99.23% (by HPLC), containing 0.10% of impurity (III) and 0.67% of impurity (IV). The same reaction, which is provided in example 10, was carried out using potassium carbonate in methanol at different reaction conditions, as depicted in Table 2.
81.1%
With potassium hydroxide In water at 20 - 65℃; for 2 - 11h;
20; 21; 22; 23; 24; 25
Example 20 - Preparation of Moxonidine by reaction of DMAIA with 45% aqueous potassium hydroxide solution at ambient temperature A mixture of DMAIA (5 g, 0.0174 mol) and 45% aqueous potassium hydroxide solution (1.8 g, 0.029 mol, 1.7 equiv.) in methanol (40 ml) was stirred at ambient temperature for 10 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to give 3.7 g of crude Moxonidine in 88.3% yield, having a purity of 99.45% (by HPLC), containing 0.03% of impurity (III) and 0.52% of impurity (IV). The same reaction, which is provided in example 20, was carried out using aqueous potassium hydroxide in methanol at different reaction conditions, as depicted in Table 5.
81.1%
With sodium hydroxide In water at 40 - 65℃; for 2 - 10h;
13; 15; 16
Example 13 - Preparation of Moxonidine by reaction of DMAIA with 1.5 equivalents of 47% aqueous solution of sodium hydroxide A mixture of DMAIA (5 g, 0.0174 mol) and 47% aqueous solution of sodium hydroxide (1.25 g, 0.026 mol, 1.5 equiv.) in methanol (40 ml) was stirred at 40-50° C for 10 hours. Then, the reaction mixture was cooled to ambient temperature and water (50 ml) was added. After stirring for one hour, a colorless precipitate was collected by filtration, washed with water (3 *10 ml) and 2-propanol (3 *10 ml) and dried at 50° C overnight to yield 3.7 g of crude Moxonidine in 88.3% yield, having a purity of 99.52% (by HPLC), containing 0.04% of impurity (III) and 0.44% of impurity (IV). The same reaction, which is provided in example 13, was carried out using sodium hydroxide solution in methanol at different reaction conditions, as depicted in Table 3.
71.1%
With sodium hydrogencarbonate at 40 - 65℃; for 14.5 - 24h;
26; 27; 28
The same reaction, which is provided in example 17, was carried out using sodium bicarbonate powder in methanol, optionally with addition of small volume of water (example 29), at different reaction conditions, as depicted in Table 6.
With potassium carbonate at 47 - 52℃; for 5h;
2 Reference Example 2
Reference Example 2 - Preparation of Moxonidine by reaction of DMAIA with 2 molar equivalents of potassium carbonate at 47-52° C. Potassium carbonate (9.6 g, 0.0694 mol, 2 molar equiv.) was added to a suspension of DMAIA (10 g, 0.0347 mol) in methanol (80 ml) and the mixture was heated at 47-52° C for 5 hours. Then, the reaction mixture was cooled to ambient temperature and acetic acid (10 ml) and water (70 ml) were added. After stirring for half an hour, 25% solution of ammonium hydroxide (10 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water and dried at 50° C overnight to yield crude Moxonidine containing 0.07% of impurity (III) and 0.40% of impurity (IV).
With potassium carbonate at 47 - 52℃; for 5h;
2 Reference Example 2
Reference Example 2 - Preparation of Moxonidine by reaction of DMAIA with 2 molar equivalents of potassium carbonate at 47-52° C. Potassium carbonate (9.6 g, 0.0694 mol, 2 molar equiv.) was added to a suspension of DMAIA (10 g, 0.0347 mol) in methanol (80 ml) and the mixture was heated at 47-52° C for 5 hours. Then, the reaction mixture was cooled to ambient temperature and acetic acid (10 ml) and water (70 ml) were added. After stirring for half an hour, 25% solution of ammonium hydroxide (10 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water and dried at 50° C overnight to yield crude Moxonidine containing 0.07% of impurity (II) and 0.40% of impurity (III).
9
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
11
The same reaction, which is provided in example 10, was carried out using potassium carbonate in methanol at different reaction conditions, as depicted in Table 2.
14
The same reaction, which is provided in example 13, was carried out using sodium hydroxide solution in methanol at different reaction conditions, as depicted in Table 3.
88.3%
With potassium hydroxide at 25℃; for 12h;
19
The same reaction, which is provided in example 17, was carried out using 85% potassium hydroxide powder in methanol at different reaction conditions, as depicted in Table 4.
5
The same reaction, which is provided in example 1, was carried out using sodium methoxide in methanol at different reaction conditions, or alternatively using other solvents than methanol, as depicted in Table 1
Stage #1: 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine With potassium carbonate In methanol at 47 - 52℃; for 5h;
Stage #2: With water; acetic acid In methanol for 0.5h;
Stage #3: With ammonia In methanol; water for 1h;
R.2
Reference Example 2 - Preparation of Moxonidine by reaction of DMAIA with potassium carbonate according to the teaching of the '649 patent. Potassium carbonate (9.6 g, 0.0694 mol, 2 molar equiv.) was added to a suspension of DMAIA (10 g, 0.0347 mol) in methanol (80 ml) and the mixture was heated at 47-52° C for 5 hours. Then, the reaction mixture was cooled to ambient temperature and acetic acid (10 ml) and water (70 ml) were added. After stirring for half an hour, 25% solution of ammonium hydroxide (10 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water and dried at 50° C overnight to yield crude Moxonidine [containing 0.07% of impurity II and 0.40% of impurity III].
With pyrographite; 1,8-diazabicyclo[5.4.0]undec-7-ene at 65℃; for 3.5h;
EXAMPLE
EXAMPLE [0057] Moxinidine was synthesized from DMAIA according to the following procedure. [0058] A 4 L glass reactor (with heating jacket) equipped with overhead stirrer, reflux condenser and internal thermometer was charged with DMAIA (149 g, 517 mmol) and activated charcoal (7.50 g). Methanol (3.45 L) and DBU (110 g, 722 mmol, 1.4 eq.) was added and the addition jar rinsed with methanol (100 mL). The jar containing DMAIA was rinsed with methanol (200 mL). The stirrer was turned on and the mixture was heated to reflux (65° C.) for 3.5 h. Then, acetic acid (14.1 g, 234 mmol, 0.45 eq) was added over 7 min. After vacuum filtration of the hot reaction mixture over a paper filter (MN 85/220) and rinsing of the filter cake with hot methanol (100 mL), the filtrate was transferred to a second reactor equipped with overhead stirrer, distillation head with condenser and internal thermometer. The temperature was set to 40-43° C. IT and seeding crystals (1.5 g) were added. A thin suspension formed while the suspension was stirred for 45 min. After further cooling to 20° C. within 1.5 h, the process was discontinued overnight. Then the mixture was concentrated by distillation in vacuo (290 mbar, ET 65° C., IT 37-38° C., dist. temp. 35-37° C., 4.25 h). 2.4 L of solvent were removed. The mixture was cooled to 4° C. within 3 h under stirring and kept at 0-5° C. for 1 h (vacuum was broken at an ET below 36° C.). The suspension was vacuum-filtered (on G4 filter frit) and the reactor rinsed with 450 mL of mother liquor (to collect the remaining product) and the filter cake (product) subsequently washed with cold methanol (120 mL), cold water (2×150 mL) and cold methanol (2×120 mL) to afford a colourless crystalline powder after drying at 60° C. for 19 h (overnight). yield: 106.2 g, 439 mmol, 84.4%. Assay (HPLC): 99.5%, Impurity A<0.05%, impurity B 0.18%, sulphated ash: 0.02%.
83.5%
With potassium hydroxide at 20℃; for 30h;
1 Example 1
Example 1 - Preparation of crude Moxonidine by an improved process, as described in a copending application A mixture of DMAIA (5 g, 0.0174 mol) and 85% potassium hydroxide powder (1.276 g, 0.019 mol, 1.1 equiv.) in methanol (40 ml) was stirred at ambient temperature for 30 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 x10 ml) and 2-propanol (3 x10 ml) and dried at 50° C overnight to give 3.5 g of crude Moxonidine in 83.5% yield, having a purity of 98.2% (by HPLC).
3.43 g
With tetrabutylammomium bromide; water; sodium hydroxide In dichloromethane at 20 - 35℃; for 2.5h;
2 Example 2 - Preparation of Moxonidine by phase transfer catalysis
Sodium hydroxide (10 ml, 50 % aqueous solution, 5.0 g, 0.125 mol) was added to a solution of DMAIA (5.0 g, 0.0174 mol, 87 % purity) in methanol (20 ml), methylene chloride (100 ml) and tetra-n-butylammonium bromide (0.32 g, 0.1 mol %). The reaction was slightly exothermic and for a quarter of an hour the temperature reached 30 °C. Then the solution was heated at 35 °C for 2 hours. The aqueous phase was separated by funnel and the solvents from the organic phase were distillated. The residue was suspended in water (50 ml) and the precipitate was collected by filtration, washed with water till pH ~7 of the washing water and dried at 50 °C. The yield of Moxonidine was 3.43 g (93.97%; toward 87% of DMAIA purity) with a purity of 99.91 %.
With potassium hydroxide In methanol; water at 20℃; for 31h;
1
Example 1 - Preparation of crude Moxonidine by an improved process, as described in a copending application A mixture of 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-amino-pyrimidine (5 g, 0.0174 mol) and 85% potassium hydroxide powder (1.276 g, 0.019 mol, 1.1 equiv.) in methanol (40 ml) was stirred at ambient temperature for 30 hours. Then, water (50 ml) was added and the mixture was stirred for one hour. A colorless precipitate was collected by filtration, washed with water (3 * 10 ml) and 2-propanol (3 * 10 ml) and dried at 50° C overnight to give 3.5 g of crude Moxonidine in 83.5% yield, having a purity of 98.2% (by HPLC).
With sodium methylate In methanol; water
3 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine
EXAMPLE 3 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine 10 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are mixed with a solution of 3.78 g sodium methylate in 35 ml methanol and boiled for 2 hours. Then 100 ml water are added, cooled, and vacuum dried. 7.2 g of 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained. (Melting point 217°-219° C., decomposition) from nitromethane. For the preparation of the hydrochloride, the base is suspended in 20 ml water and brought with hydrochloric acid to a pH of 3.
In tetrahydrofuran; methanol
25 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine
EXAMPLE 25 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine 10.0 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are boiled in 400 ml methanol for 48 hours under reflux. The solution is concentrated, and the residue mixed with warm tetrahydrofuran. The crystals are recrystallized from isopropanol/ether. 6.4 g (80%) of 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained as the hydrochloride, melting point 189° C. Melting point of the base 217°-219° C. (decomposition). 1 H-NMR spectrum is DMSO-d6, delta values in ppm: 2.53 (s, CH3), 3.65 (s, N-CH2 --CH2 -N), 3.98 (s, OCH3), 8.66 (twice NH, deuterizable).
4
EXAMPLE 4[0054] This example describes the preparation of moxonidine from DMAIA containing 5.7% of iso-DMAIA.[0055] A mixture of DMAIA (5.0 g), iso-DMAIA (0.3 g), methanol (25 ml) and 25% sodium methoxide solution in methanol (3.9 mi, 1.1 equiv.) was stirred at ambient temperature overnight. A sample of the reaction mixture was withdrawn and analyzed by HPLC indicating that the reaction mixture contained 87.9% of moxonidine and 9.7% of compound (VI). Water (50 ml) was then added to the reaction mixture and stirring was maintained at ambient temperature for 4 hours. A precipitate was collected by filtration, washed with water and 2-propanol and dried at 60° C overnight to yield 3.9 g of crude Moxoϖidine in 73.6% yield, having a purity of 96.66% and containing 0.12% of the impurity VI (by HPLC).
1
COMPARATIVE EXAMPLE 1[0041] This example describes the preparation and purification of moxonidine as described in the '570 patent.[0042] 4,6~dicHoro-2-methyl-5-(l-acetyl-2-imidazoHn-2-yl)-aminopyrimidine (10 g) was mixed with a solution of sodium methoxide (NaOCHs) (3.78 g) in methanol (35 ml) and xefluxed for 2 hours. A sample was withdrawn, diluted with the HPLC eluent mixture and injected to the HPLC system. The sample contained 93.25% of moxonidine, 1.48% of 4,6- dichloro-2-niethyl-5-(2-imidazolin-2-yl)-aminopyrimidine (compound VII) and 5.27% of 4,6- dimethoxy-2-methyl-(2-imidazolin-2-yl)-aminopyrimidine (compound VIII). Then, water (100 ml) was added, and the mixture was cooled and vacuum dried. A sample of the thus obtained solid was taken, dissolved in the HPLC eluent mixture and injected to the HPLC system. The sample contained 93.22% of moxonidine, 1.45% of 4,6-dichloro-2-metliyl-5-(2- imidazolin-2-yl)-aminopyrimidine and 5.32% of 4,6-dimethoxy-2-methyl-(2-imidazolin-2- yl)-aminopyrimidine. The solid was heated under reflux in nitromethane (250 ml) for half an hour and the hot mixture was filtered. The filtrate was kept at 5°C overnight. A colorless precipitate was collected by filtration, washed with ethyl acetate and dried at 600C overnight to yeld 7.1 g of moxonidine having 93.44% purity by HPLC and containing 1.19% of 4,6- dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine and 5.37% of 456-dimethoxy-2~ methyl-(2-imidazolin-2-yl)-aminopyrimidine.
EXAMPLE 1[0043] This example describes the preparation of 4,6-dichloro-2-methyl-5-(l -acetyl-2- imidazolin -2-yl)-aminopyrimidine (DMAIA).[0044] A mixture of 5-amino-4-6-dichloro-2-me11iylpyrimidine (50 g, 0.281 moles, 1 equiv.), l-acetyl-2-midazolidin-2-one (40 g> 0.357 moles, 1.27 equiv.) and phosphorous oxychloride (75 ml, 0.804 moles, 2.86 equiv.) was heated at ~90 C for 7 hours and then cooled to room temperature. The reaction mixture and 46% aqueous sodium hydroxide <n="14"/>solution (200 ml) were added drop-wise simultaneously from two separate dropping funnels to a 1 liter flask, fitted with a stirrer and containing cold water (300 ml), in such a pace that kept the internal temperature below 70 C and pH below 10. The reaction mixture was cooled to 45 C and a precipitate was collected by filtration and washed with water (200 ml). The precipitate was dried at 800C to obtain 55 g of a solid (containing 55% of DMAIA and 35% of iso-DMAIA, according to HPLC).[0045] rhe solid was dissolved in DMSO (165 ml) at 90 C and activated charcoal (1.4 g) was added to the solution. The mixture was stirred at 90 C for 0.5 hours and then filtered. The filtrate was heated to 90 C and water (38 ml) was added drop-wise. The mixture was cooled to 5 C and kept at this temperature overnight. A solid was separated from the filtrate and collected by filtration, washed with water and 2-propanol and dried at 800C to obtain 21.1 g of DMAIA, having a purity of 93% (by HPLC).
Phosphorus oxychloride (1500 ml), 4,6-dichloro-2-methyl-5-pyrimidinamine (500 gm) and 1-acetyl-2-imidazolidine-2-one (400 gm) were added at room temperature. The contents were heated to 50C, maintained for 48 hours and the phosphorus oxychloride was distilled under vacuum at below 45C. The reaction mass was poured into chilled water at 5C for 1 hour to 1 hour 30 minutes. The pH of the reaction mass was adjusted to 8.5 with potassium carbonate solution, stirred for 30 minutes and filtered. The solid thus obtained was added methanol (8750 ml) and ethyl acetate (8750 ml) at room temperature. The contents were heated to reflux and treated with carbon. The reaction mass was filtered through ciliate bed and then dried to obtain 560 gm of 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)aminopyrimidine.
2 Example 2: Preparation of moxonidine
Methanol (18000 ml) was added to 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)aminopyrimidine (600 gm) at room temperature and then heated to 30 to 35°C. To the reaction mass was added sodium methoxide (600 gm) slowly for 45 minutes. The solvent was distilled under vacuum below 30°C to obtain a residual solid and then added water (5500 ml). The reaction mass was stirred for 10 minutes and filtered. The solid thus obtained was dried to get 520 gm of moxonidine.Chromatographic purity of moxonidine: 99.78%;Content of 6-chloromoxonidine: 0.03%;Content of 4-methoxymoxonidine: 0.15%.
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