* 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.
To the suspension of 1.3 g (2.5 [MMOL)] of compound [(VIII)] and 3 ml of water 12 m of [1 37percent] aqueous hydrochloric acid solution is added. The obtained solution is stirred at 40 [C] for 3 hours, cooled to 10 [C] and 38 mi of 4 M aqueous sodium hydroxide solution added dropwise. The precipitated mosapride base of formula IX is filtered, washed 2 x with water, to give 1.05 g (100percent) of the compound of formula [(IX).] 1.01 g of mosapride base of formula [(IX)] obtained the above manner is warmed to boiling with 25 [ML] of 10percent aqueous citric acid solution with stirring, cooled to 0 [C,] the precipitated product filtered, washed 2 x with water to give 1.34 g (86 percent) of the title compound. Mp: [110-113C.]
Citric acid monohydrate (84.67 g) and water (850 ml) were charged at ambient temperature and stirred to dissolve the solid. The reaction mass was heated up to 80°C and mosapride free base (85 g) was charged at 80°C. The heterogeneous mass was stirred and heated up to reflux (95 °C to 110°C). The clear solution was stirred at reflux temperature for 30 minutes. The reaction mass was cooled down to 0°C and was stirred at 0°C to 5°C for 30 minutes. The solid was filtered and washed with water (2 X 170 ml). The solid was suck dried and unloaded. The solid was dried at 60°C for 15 hours under vacuum to give the title compound.Yield: 125 g (95.45percent)Water content: 6.28percentD-II Impurity: 0.269
94.7%
at 50℃; for 1 h;
General procedure: Stirring blade, three-necked flask 100mL fitted with a thermometer, HPLC and thepurity 99.94percent of the amide compound 10.0g (23.8mmol) prepared in Preparation Example 1,ethanol 80g, and water 80g was added, stirring to obtain a slurry. The resulting slurry waswarmed to 50 ° C. Then, 13.6g citric acid (71.2mmol) was dropped to gradually the slurry overa period of (temperature 50 ° C of the aqueous solution) for 10 minutes aqueous solution ofcitric acid dissolved in water 20g, amide compound and citric acid was reacted (the temperatureof the reaction solution at the time of aqueous citric acid dropwise addition was adjusted to 50 °C (reaction temperature 50 ° C)). After the aqueous solution of citric acid dropping, and allowedto react for 1 hour at 50 ° C (reaction temperature 50 ° C. The reaction solution wasconfirmed by visual observation that became clear during this time. ). Thereafter, the resultantreaction solution was cooled slowly to 10 ° C, and held for 1 hour. The precipitated solid wasfiltered off by vacuum filtration and the cake was washed twice with water 30g. Obtained afterdrying under reduced pressure a white solid at an external temperature of 40 ° C, as a whitesolid 4-amino-5-chloro-2-ethoxy -N - [[4- (4-fluoro-benzyl) -2-morpholinyl] methyl] It wasobtained benzamide citrate 2 hydrate (citrate dihydrate) 14.1g (21.8mmol). Yield: 91.4percent, HPLCpurity: 99.94percent, by-products: (not detected) undetected, water content: 5.8percent, quantitative value:was 100.5percent. The results are shown in Table 1. Incidentally, the yield of citrate dihydrate is avalue obtained by measuring the mass of simply obtained solid.
With hydrogenchloride In water at 40℃; for 3 h; Alkaline aqueous solution
To the suspension of 1.3 g (2.5 [MMOL)] of compound [(VIII)] and 3 ml of water 12 m of [1 37percent] aqueous hydrochloric acid solution is added. The obtained solution is stirred at 40 [C] for 3 hours, cooled to 10 [C] and 38 mi of 4 M aqueous sodium hydroxide solution added dropwise. The precipitated mosapride base of formula IX is filtered, washed 2 x with water, to give 1.05 g (100percent) of the compound of formula [(IX).] 1.01 g of mosapride base of formula [(IX)] obtained the above manner is warmed to boiling with 25 [ML] of 10percent aqueous citric acid solution with stirring, cooled to 0 [C,] the precipitated product filtered, washed 2 x with water to give 1.34 g (86 percent) of the title compound. Mp: [110-113C.]
Stage #1: With benzyl chloroformate; triethylamine In dichloromethane at -5 - 0℃; for 3.66 h; Inert atmosphere Stage #2: at -5 - 20℃; for 1.66 h; Inert atmosphere
Stirring blade, three-neckedflask 100mL fitted with a thermometer, a nitrogen atmosphere, were dissolved 4-amino-5-chloro-2-ethoxy-benzoic acid 50.0g (233.3mmol) in methylene chloride 1000 mL, triethylamine afterthe addition of 24.7g (243.3mmol), reaction of benzyl chloroformate 43.3g (243.3mol)temperature was added dropwise over a period as 40 minutes less than or equal to -5 ° C. Then,the mixture was stirred for 3 hours at 0 ° C. The reaction mixture obtained under a nitrogen atmosphere, to a 1000mL of methylene chloridesolution of 2 was cooled to below -5 ° C (aminomethyl) -4- (4-fluorobenzyl) morpholine 53.3g(233.3mmol) , the reaction temperature was added dropwise over 40 min to be equal to or lessthan -5 ° C. After stirring for 1 hour at room temperature, water 1000mL was added, followedby shaking with a separating funnel, the organic layer was separated. In addition, a 10 mass percentaqueous solution of sodium hydroxide 2000g In addition, the same procedure was carried out.The obtained organic layer was washed two times with ion-exchanged water 1500 mL, organiclayer was concentrated and the white solid was obtained 120.0 g. After the resulting white solid was dissolved by adding dimethylformamide 1157mL, water wasadded 267 ml. Gradually performed cooled to 5 ° C, held for 2 hours at 5 ° C, and theprecipitated crystals by filtration. The resulting white crystals were dried under reducedpressure, as a high-purity white crystalline 4-amino-5-chloro-2-ethoxy--N - [[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (amide compound) was obtained 66.0g of the (156.3mmol).67.0percent yield, was HPLC purity 99.94percent.
Reference：
[1] Patent: JP5743474, 2015, B2, . Location in patent: Paragraph 0062-0064
[2] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 616 - 624
5
[ 112913-96-9 ]
[ 112885-41-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 616 - 624
Stirring blade, three-neckedflask 100mL fitted with a thermometer, a nitrogen atmosphere, were dissolved 4-amino-5-chloro-2-ethoxy-benzoic acid 50.0g (233.3mmol) in methylene chloride 1000 mL, triethylamine afterthe addition of 24.7g (243.3mmol), reaction of benzyl chloroformate 43.3g (243.3mol)temperature was added dropwise over a period as 40 minutes less than or equal to -5 C. Then,the mixture was stirred for 3 hours at 0 C. The reaction mixture obtained under a nitrogen atmosphere, to a 1000mL of methylene chloridesolution of 2 was cooled to below -5 C (aminomethyl) -4- (4-fluorobenzyl) morpholine 53.3g(233.3mmol) , the reaction temperature was added dropwise over 40 min to be equal to or lessthan -5 C. After stirring for 1 hour at room temperature, water 1000mL was added, followedby shaking with a separating funnel, the organic layer was separated. In addition, a 10 mass%aqueous solution of sodium hydroxide 2000g In addition, the same procedure was carried out.The obtained organic layer was washed two times with ion-exchanged water 1500 mL, organiclayer was concentrated and the white solid was obtained 120.0 g. After the resulting white solid was dissolved by adding dimethylformamide 1157mL, water wasadded 267 ml. Gradually performed cooled to 5 C, held for 2 hours at 5 C, and theprecipitated crystals by filtration. The resulting white crystals were dried under reducedpressure, as a high-purity white crystalline 4-amino-5-chloro-2-ethoxy--N - [[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (amide compound) was obtained 66.0g of the (156.3mmol).67.0% yield, was HPLC purity 99.94%.
Example 3; Synthesis of 4-amino-5-chloro-2-ethoxy-N-(morpholin-2-ylmethyl)benzamide (21). Intermediate 21 was prepared as outlined in Scheme VI below. Details of the synthesis are set forth below. Synthesis of 4-amino-2-ethoxy-N-(morpholin-2-ylmethyl)benzamide (18). A suspension of commercially available benzamide 17 (3.00 g, 7.1 mmol) in EtOH (75 mL) was purged with N2, followed by the addition of Pd/C (38 mg, 0.355 mmol, 0.05 equiv). The N2 atmosphere was evacuated and replaced by H2 and the resulting mixture was stirred overnight. Due to incomplete conversion, additional Pd/C (800 mg) was added to the flask and stirring at RT under H2 was continued overnight. After this time, due to incomplete conversion, acetic acid (6 mL) was added and stirring of the reaction mixture at 50 C. under H2 was continued overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to a yellow oil. The oil was dissolved in water then made basic by the addition of 10% NaOH. The resulting precipitate was filtered, washed with H2O then dried under vacuum to yield product 18 (1.78 g).
With citric acid; In water; at 0℃;Heating / reflux;
To the suspension of 1.3 g (2.5 [MMOL)] of compound [(VIII)] and 3 ml of water 12 m of [1 37%] aqueous hydrochloric acid solution is added. The obtained solution is stirred at 40 [C] for 3 hours, cooled to 10 [C] and 38 mi of 4 M aqueous sodium hydroxide solution added dropwise. The precipitated <strong>[112885-41-3]mosapride</strong> base of formula IX is filtered, washed 2 x with water, to give 1.05 g (100%) of the compound of formula [(IX).] 1.01 g of <strong>[112885-41-3]mosapride</strong> base of formula [(IX)] obtained the above manner is warmed to boiling with 25 [ML] of 10% aqueous citric acid solution with stirring, cooled to 0 [C,] the precipitated product filtered, washed 2 x with water to give 1.34 g (86 %) of the title compound. Mp: [110-113C.]
With hydrogenchloride; In water; at 40℃; for 3h;Alkaline aqueous solution;
To the suspension of 1.3 g (2.5 [MMOL)] of compound [(VIII)] and 3 ml of water 12 m of [1 37%] aqueous hydrochloric acid solution is added. The obtained solution is stirred at 40 [C] for 3 hours, cooled to 10 [C] and 38 mi of 4 M aqueous sodium hydroxide solution added dropwise. The precipitated mosapride base of formula IX is filtered, washed 2 x with water, to give 1.05 g (100%) of the compound of formula [(IX).] 1.01 g of mosapride base of formula [(IX)] obtained the above manner is warmed to boiling with 25 [ML] of 10% aqueous citric acid solution with stirring, cooled to 0 [C,] the precipitated product filtered, washed 2 x with water to give 1.34 g (86 %) of the title compound. Mp: [110-113C.]
The organic layer is treated in the same manner as in part (2) of this Reference Example to give the title compound. Various compounds used as starting materials in Examples 86 to 95, and 97 to 123 are prepared in substantially the same manner as in this Reference Example, using the appropriate agents in place of hexyl iodide.
4-amino-5-chloro-N-[[4-(2-chlorobenzyl)-6-methyl-2-morpholinyl]methyl]-2-ethoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
(2) The free base (2.6 g) obtained in part (1) of this Example is dissolved in ethanol (50 ml), and a solution of fumaric acid (1.5 g) in ethanol (20 ml) is added. The resulting solution is concentrated to about 10 ml. The precipitate is collected and recrystallized from isopropyl alcohol to give the difumarate of the title compound, mp 150-154 C.
at 80 - 110℃; for 0.5h;Product distribution / selectivity;
Citric acid monohydrate (84.67 g) and water (850 ml) were charged at ambient temperature and stirred to dissolve the solid. The reaction mass was heated up to 80C and <strong>[112885-41-3]mosapride</strong> free base (85 g) was charged at 80C. The heterogeneous mass was stirred and heated up to reflux (95 C to 110C). The clear solution was stirred at reflux temperature for 30 minutes. The reaction mass was cooled down to 0C and was stirred at 0C to 5C for 30 minutes. The solid was filtered and washed with water (2 X 170 ml). The solid was suck dried and unloaded. The solid was dried at 60C for 15 hours under vacuum to give the title compound.Yield: 125 g (95.45%)Water content: 6.28%D-II Impurity: 0.269
94.7%
In ethanol; water; at 50℃; for 1h;
General procedure: Stirring blade, three-necked flask 100mL fitted with a thermometer, HPLC and thepurity 99.94% of the amide compound 10.0g (23.8mmol) prepared in Preparation Example 1,ethanol 80g, and water 80g was added, stirring to obtain a slurry. The resulting slurry waswarmed to 50 C. Then, 13.6g citric acid (71.2mmol) was dropped to gradually the slurry overa period of (temperature 50 C of the aqueous solution) for 10 minutes aqueous solution ofcitric acid dissolved in water 20g, amide compound and citric acid was reacted (the temperatureof the reaction solution at the time of aqueous citric acid dropwise addition was adjusted to 50 C (reaction temperature 50 C)). After the aqueous solution of citric acid dropping, and allowedto react for 1 hour at 50 C (reaction temperature 50 C. The reaction solution wasconfirmed by visual observation that became clear during this time. ). Thereafter, the resultantreaction solution was cooled slowly to 10 C, and held for 1 hour. The precipitated solid wasfiltered off by vacuum filtration and the cake was washed twice with water 30g. Obtained afterdrying under reduced pressure a white solid at an external temperature of 40 C, as a whitesolid 4-amino-5-chloro-2-ethoxy -N - [[4- (4-fluoro-benzyl) -2-morpholinyl] methyl] It wasobtained benzamide citrate 2 hydrate (citrate dihydrate) 14.1g (21.8mmol). Yield: 91.4%, HPLCpurity: 99.94%, by-products: (not detected) undetected, water content: 5.8%, quantitative value:was 100.5%. The results are shown in Table 1. Incidentally, the yield of citrate dihydrate is avalue obtained by measuring the mass of simply obtained solid.
1) Preparation of Particle Comprising Mosapride Mosapride-containing particles were prepared as described in Example 8-2 using mosapride citrate instead of famotidine.
1) Preparation of particle comprising mosapride Mosapride-containing particles were prepared as described in Example 8-2 using mosapride citrate instead of famotidine.
With iron; ammonium chloride In ethanol; water for 5h; Reflux;
8; 9 Example 8: Synthesis of 4-amino-5-chloro-2-ethoxy-N-((4-(4-fluorophenyl)morpholin-2-yl)methyl)benzamide
Add 4-nitro-5-chloro-2-ethoxy-N-((4-(4-fluorophenyl)morpholin-2-yl)methyl)benzamide (63.3g, 0.14 mol), iron powder(27.4g, 0.49mol) and ammonium chloride (11.2g, 0.21mol) were added to480mL ethanol and 120mL water, reflux for 5h, cool, filter,Most of the ethanol was evaporated from the filtrate, 600mL ethyl acetate was added,Wash with 600mL water, evaporate ethyl acetate,Recrystallize the obtained crude product with ethyl acetate/n-heptane to obtain57.0 g of light yellow solid, with a yield of 96.5%.
Multi-step reaction with 4 steps
1: ethanol / 4 h / 40 °C
2: iron(III) chloride; N-chloro-succinimide / N,N-dimethyl-formamide / 4 h / 50 °C
3: N,N-dimethyl-formamide / 6 h / 100 °C
4: iron; ammonium chloride / ethanol; water / 5 h / Reflux
Multi-step reaction with 4 steps
1: ethanol / 4 h / 40 °C
2: iron(III) chloride; N-chloro-succinimide / N,N-dimethyl-formamide / 4 h / 50 °C
3: triethylamine / N,N-dimethyl-formamide / 6 h / 100 °C
4: iron; ammonium chloride / ethanol; water / 5 h / Reflux
With di-tert-butyl peroxide; iodine In acetonitrile at 70℃; for 8h;
1.7 Step 7: Synthesis of Mosapride (VII)
Take 11 grams of 2-ethoxy-4-amino-5-chlorobenzyl methyl ether, 14g2-Aminomethyl-4-(4-fluorobenzyl)morpholine, 60ml acetonitrile,40g tert-butanol peroxide (TBHP), 1g iodine, react at 70° for 8h, after the reaction,Cool to room temperature, add 30 grams of sodium bisulfite to the reaction system,60ml water, 50ml ethyl acetate extraction,Wash the organic layer twice with water, dry the organic layer with anhydrous sodium sulfate, filter,The filtrate was distilled under reduced pressure to obtain a white crude product, which was recrystallized from 70% ethanol15.5 g of white solid was obtained, and the yield was 74%.
With lithium hydroxide monohydrate In methanol; butan-1-ol at 20 - 50℃; for 36.1667h; Sonication;
1-7 Example 1
Dissolve 200 mg of mosapride and 130.0 mg of vanillic acid in 17.2 mL of mixed solvent (13 mL of methanol, 0.2 mL of water and 4 mL of n-butanol), ultrasonically heat to 50 °C, continue to ultrasonicate for 10 min after dissolving, filter, and let it stand at 20-25 °C Set to crystallize for 36 hours, filter, and dry at 45°C for 40 hours to obtain 268.0 mg of mosapride-vanillic acid co-crystal hydrate. The yield was 92.96%, and the purity was 99.96%.
With aminosulfonic acid In ethanol; lithium hydroxide monohydrate; propan-2-one at 60℃;
6-10 Example 6
2.5 g of mosapride and 0.69 g of sulfamic acid were dissolved in 132 mL of mixed solvent (80 mL of acetone, 40 mL of ethanol and 12 mL of water), heating to 60°C, after dissolving, filtering, controlling the temperature to 6-9°C for crystallization for 45 hours, filtering, rinsing the filter cake with ethanol, drying the filter cake at 60°C for 15 hours, to obtain 3.12 g of mosapride aminosulfonic acid Acid trihydrate. The yield was 92.25%, and the purity was 99.92%.
1-5 Example 1
2.5 g of mosapride and 1.8 g of 5-sulfosalicylic acid were dissolved in 120 mL of mixed solvent (40 mL of methanol, 40 mL of acetone and 40 mL of ethanol), heated to 60°C, dissolved, filtered, and the temperature was controlled to 6-9°C Crystallization for 45 hours, Filter, rinse the filter cake with methanol, and dry the filter cake at 60° C. for 15 h to obtain 3.62 g of mosapride 5-sulfosalicylate methanolate. The yield is 93.50%, and the purity is 99.97%.
1-5 Example 1
Dissolve 2.5 g of mosapride and 0.72 g of maleic acid in 120 mL of mixed solvent (100 mL of acetone and 20 mL of methanol), heat to 50°C, dissolve, filter, and control the temperature to -5-1°C for crystallization for 5 hours. Filter, rinse the filter cake with methanol, and dry the filter cake at 60° C. for 10 h to obtain 2.96 g of mosapride maleate. The yield was 92.82%, and the purity was 99.92%.
6-10 Example 6
Dissolve 2.5 g of mosapride and 0.97 g of tartaric acid in 120 mL of mixed solvent (80 mL of tert-butanol and 40 mL of methanol), heat to 50°C, dissolve, filter, control the temperature to -5-1°C for crystallization for 6 hours, and filter , rinse the filter cake with methanol, and dry the filter cake at 55 ° C for 10 h to obtain 3.41 g of tartaric acid eutectic methanolate of mosapride. The yield was 90.75%, and the purity was 99.91%.
In methanol; tetrahydrofuran-d8 at 6 - 60℃; for 8.5h;
1-5 Example 1
Dissolve 2.5 g of mosapride and 0.59 g of oxalic acid in 100 mL of mixed solvent (50 mL of methanol + 50 mL of tetrahydrofuran), heat to 60°C, dissolve, filter, control the temperature to 6-8°C for crystallization for 8.5 hours, filter, rinse with methanol The filter cake was washed, and the filter cake was dried at 70° C. for 12 hours to obtain 2.85 g of mosapride oxalate. The yield was 94.2%, and the purity was 99.96%.
With lithium hydroxide monohydrate at 10 - 75℃; for 11h;
6-10 Example 6
Dissolve 5.0 g of mosapride and 1.1 g of gallic acid in 170 mL of mixed solvent (85 mL of methanol + 85 mL of water), heat to 75°C, dissolve, filter, control the temperature to 10-12°C for crystallization for 11 hours, filter, use methanol The filter cake was rinsed, and the filter cake was dried at 70° C. for 13 hours to obtain 5.78 g of mosapride gallic acid eutectic methanol monohydrate. The yield was 92.11%, and the purity was 99.92%.
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