* 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.]
Stage #1: With sodium hydroxide In dichloromethane; water for 0.5 h; Heating / reflux Stage #2: at 0℃; for 0.5 h; Heating / reflux
1.04 g (2 [MMOL)] of compound [(VIII)] and 15 mi of 1.77 M hydrochloric acid in ethyl acetate are stirred at 50 [C] for 2 hours and at 0 [C] for 2 hours. The precipitated crystals are filtered and washed 2 x with cooled ethyl acetate to give 0.93 g (94 percent) mosapride dihydrochloride. Mp. 144-155 [C.] To the mosapride [DIHYDROCHLORIDE] salt obtained the above manner, 20 ml of [DICHLOROMETHANE,] 10 [ML] of water and 1.2 [ML] of 4 M aqueous sodium hydroxide solution are added. The organic phase is separated and the aqueous phase extracted with [2X10] [ML] of [DICHLOROMETHANE.] The combined organic phases are dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure. To the residue 23 [ML] of 10percent aqueous citric acid solution is added, refluxed for 30 minutes and cooled to 0 [C.] The precipitated product is filtered and washed 2 x with water to give 0.91 g (88percent) of the title compound. Mp : [110-113 C.]
Stage #1: With sodium hydroxide In dichloromethane; water Stage #2: With citric acid In water
The solution of 1.04 g (2 [MMOL)] of compound [(VIII),] 13 ml of [DICHLOROMETHANE] and 0.77 mi of trifluoroacetic acid is stirred at room temperature for 6 hours. The reaction mixture is evaporated under reduced pressure, crystallized from ether, filtered and washed with ether to give 1.01 g (94 percent) trifluoroacetate salt of the title compound. Mp: [186-193C.] 0.99 g (1.85 [MMOL)] of mosapride trifluoroacetate salt obtained the above manner is treated substantially the same manner as in Example A) to give 0,99 g (83percent) of citrate dihydrate salt of the title compound. Mp: [110-113C.]
4-Acetylamino-5-chloro-2-ethoxy-n-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (20.00 g, 0.046 mol)Into a reaction flask containing 200 ml of methanol,The solution was heated and refluxed at 65 ° C, dissolved completely, cooled to 50 ° C, and an aqueous solution of citric acid was added.The reaction is kept for 30-45 minutes. After the reaction, the temperature is lowered, crystallization, suction filtration,Mosapride citrate was obtained (yield 88.7percent, purity 99.93percent).
Reference:
[1] Patent: CN108341788, 2018, A, . Location in patent: Paragraph 0069; 0070; 0074; 0079; 0080; 0081-0087
5
[ 112885-41-3 ]
[ 77-92-9 ]
[ 112885-42-4 ]
Yield
Reaction Conditions
Operation in experiment
95.45%
at 80 - 110℃; for 0.5 h;
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 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.]
Stage #1: (RS)-4-amino-5-chloro-2-ethoxy-N-[4-(4-fluoro-benzyl)-2-morpholinyl]-methyl}-benzamide trifluoroacetate With sodium hydroxide In dichloromethane; water
Stage #2: With citric acid In water
6.B Example 6; Synthesis of (R,S)-4-amino-5-chloro-2-ethoxy-N-[4-(4-fluoro-benzyl)-2-morpholinyl]-methyl}-benzamine] citrate dihydrate (mosapride citrate dihydrate) (I); B.)
The solution of 1.04 g (2 [MMOL)] of compound [(VIII),] 13 ml of [DICHLOROMETHANE] and 0.77 mi of trifluoroacetic acid is stirred at room temperature for 6 hours. The reaction mixture is evaporated under reduced pressure, crystallized from ether, filtered and washed with ether to give 1.01 g (94 %) trifluoroacetate salt of the title compound. Mp: [186-193C.] 0.99 g (1.85 [MMOL)] of mosapride trifluoroacetate salt obtained the above manner is treated substantially the same manner as in Example A) to give 0,99 g (83%) of citrate dihydrate salt of the title compound. Mp: [110-113C.]
Stage #1: (RS)-4-amino-5-chloro-2-ethoxy-N-[4-(4-fluoro-benzyl)-2-morpholinyl]-methyl}-benzamide dihydrochloride With sodium hydroxide In dichloromethane; water for 0.5h; Heating / reflux;
Stage #2: citric acid In water at 0℃; for 0.5h; Heating / reflux;
6.A Example 6; Synthesis of (R,S)-4-amino-5-chloro-2-ethoxy-N-[4-(4-fluoro-benzyl)-2-morpholinyl]-methyl}-benzamine] citrate dihydrate (mosapride citrate dihydrate) (I); A.)
1.04 g (2 [MMOL)] of compound [(VIII)] and 15 mi of 1.77 M hydrochloric acid in ethyl acetate are stirred at 50 [C] for 2 hours and at 0 [C] for 2 hours. The precipitated crystals are filtered and washed 2 x with cooled ethyl acetate to give 0.93 g (94 %) mosapride dihydrochloride. Mp. 144-155 [C.] To the mosapride [DIHYDROCHLORIDE] salt obtained the above manner, 20 ml of [DICHLOROMETHANE,] 10 [ML] of water and 1.2 [ML] of 4 M aqueous sodium hydroxide solution are added. The organic phase is separated and the aqueous phase extracted with [2X10] [ML] of [DICHLOROMETHANE.] The combined organic phases are dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure. To the residue 23 [ML] of 10% aqueous citric acid solution is added, refluxed for 30 minutes and cooled to 0 [C.] The precipitated product is filtered and washed 2 x with water to give 0.91 g (88%) of the title compound. Mp : [110-113 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.
Multi-step reaction with 5 steps
1: water / 4 h / 45 °C
2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C
3: N-chloro-succinimide / N,N-dimethyl-formamide / 3 h / 80 °C
4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
5: methanol; water / 50 - 65 °C
Multi-step reaction with 5 steps
1: water / 4 h / 45 °C
2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C
3: N-chloro-succinimide / N,N-dimethyl-formamide / 3 h / 80 °C
4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
5: methanol; water / 50 - 65 °C
Multi-step reaction with 5 steps
1: water / 4 h / 45 °C
2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C
3: N-chloro-succinimide / N,N-dimethyl-formamide / 3 h / 80 °C
4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
5: methanol; water / 50 - 65 °C
Multi-step reaction with 5 steps
1: water / 4 h / 45 °C
2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C
3: N-chloro-succinimide / N,N-dimethyl-formamide / 3 h / 80 °C
4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
5: methanol; water / 50 - 65 °C
Multi-step reaction with 5 steps
1: water / 4 h / 45 °C
2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C
3: N-chloro-succinimide / N,N-dimethyl-formamide / 3 h / 80 °C
4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
5: methanol; water / 50 - 65 °C
Multi-step reaction with 4 steps
1.1: sodium tetrahydroborate / methanol / 4 h / 65 °C
2.1: 3 h / 70 - 80 °C
2.2: 2.5 h / 70 - 145 °C
2.3: 1.5 h
3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
4.1: methanol; water / 50 - 65 °C
Multi-step reaction with 4 steps
1.1: sodium tetrahydroborate / methanol / 4 h / 65 °C
2.1: 3 h / 70 - 80 °C
2.2: 2.5 h / 70 - 145 °C
2.3: 1.5 h
3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
4.1: methanol; water / 50 - 65 °C
Multi-step reaction with 4 steps
1.1: sodium tetrahydroborate / methanol / 4 h / 65 °C
2.1: 3 h / 70 - 80 °C
2.2: 2.5 h / 70 - 145 °C
2.3: 1.5 h
3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
4.1: methanol; water / 50 - 65 °C
Multi-step reaction with 4 steps
1.1: sodium tetrahydroborate / methanol / 4 h / 65 °C
2.1: 3 h / 70 - 80 °C
2.2: 2.5 h / 70 - 145 °C
2.3: 2 h
3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
4.1: methanol; water / 50 - 65 °C
Multi-step reaction with 4 steps
1.1: sodium tetrahydroborate / methanol / 4 h / 65 °C
2.1: 3 h / 70 - 80 °C
2.2: 2.5 h / 70 - 145 °C
3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
4.1: methanol; water / 50 - 65 °C
12 Example 12 Preparation of Mosapride Citrate:
4-Acetylamino-5-chloro-2-ethoxy-n-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (20.00 g, 0.046 mol)Into a reaction flask containing 200 ml of methanol,The solution was heated and refluxed at 65 ° C, dissolved completely, cooled to 50 ° C, and an aqueous solution of citric acid was added.The reaction is kept for 30-45 minutes. After the reaction, the temperature is lowered, crystallization, suction filtration,Mosapride citrate was obtained (yield 88.7%, purity 99.93%).
Multi-step reaction with 3 steps
1.1: 3 h / 70 - 80 °C
1.2: 2.5 h / 70 - 145 °C
1.3: 1.5 h
2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
3.1: methanol; water / 50 - 65 °C
Multi-step reaction with 3 steps
1.1: 3 h / 70 - 80 °C
1.2: 2.5 h / 70 - 145 °C
1.3: 1.5 h
2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
3.1: methanol; water / 50 - 65 °C
Multi-step reaction with 3 steps
1.1: 3 h / 70 - 80 °C
1.2: 2.5 h / 70 - 145 °C
1.3: 1.5 h
2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
3.1: methanol; water / 50 - 65 °C
Multi-step reaction with 3 steps
1.1: 3 h / 70 - 80 °C
1.2: 2.5 h / 70 - 145 °C
1.3: 2 h
2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
3.1: methanol; water / 50 - 65 °C
Multi-step reaction with 3 steps
1.1: 3 h / 70 - 80 °C
1.2: 2.5 h / 70 - 145 °C
2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap; triethylamine / dichloromethane / 1 h / -10 - -5 °C
3.1: methanol; water / 50 - 65 °C
1 Example 1 Preparation of related substances
Step 1: Take mosapride citrate raw material and citric acid in the same weight ratio and place them at 105°C for 17 hours to obtain crude impurities;Step 2: After dissolving in 20% acetonitrile aqueous solution, diluting with one-fold water to prepare a solution with a concentration of 0.03g/ml, filtering through a 0.45μm filter membrane as an impurity to prepare a test solution;Step 3: Put the test solution obtained in step 2 into high performance liquid chromatography for separation;The injection volume is 100ml, the flow rate is 250ml/min, and the detection wavelength is 274nm.Using acetonitrile-0.1% acetic acid aqueous solution (1:1) as the mobile phase, two target peaks were collected,Target peak 1 peaks at about 14.1 min, target peak 2 peaks at about 15.6 min,When the two target peaks are detected by the UV detector, start to collect fractions after the column.Enrich the sample solution; repeat this step once.Step 4: Use a rotary evaporator to concentrate the enriched sample solution of the target segment that is qualified in step 3 at 40°C until there is no acetonitrile fraction.After enriching the product concentrate with C18,90% methanol (add 0.1% formic acid) resolve the product to complete,The analytical solution was concentrated on a rotary evaporator at 40°C until there was no methanol fraction, and then stood still for crystallization.Aqueous membrane filtration is used to obtain a solid, which is dried to constant weight by blowing at 40°C to obtain related substance I and related substance II.
Multi-step reaction with 5 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
5: ethanol; water / 2 h / 20 °C
Multi-step reaction with 5 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
5: ethanol; water / 2 h / 20 °C
Multi-step reaction with 6 steps
1: sulfuric acid / 4 h / Reflux
2: ethanol / 4 h / 40 °C
3: iron(III) chloride; N-chloro-succinimide / N,N-dimethyl-formamide / 4 h / 50 °C
4: N,N-dimethyl-formamide / 6 h / 100 °C
5: iron; ammonium chloride / ethanol; water / 5 h / Reflux
6: ethanol; water / 2 h / 20 °C
Multi-step reaction with 6 steps
1: sulfuric acid / 4 h / Reflux
2: ethanol / 4 h / 40 °C
3: iron(III) chloride; N-chloro-succinimide / N,N-dimethyl-formamide / 4 h / 50 °C
4: triethylamine / N,N-dimethyl-formamide / 6 h / 100 °C
5: iron; ammonium chloride / ethanol; water / 5 h / Reflux
6: ethanol; water / 2 h / 20 °C
Multi-step reaction with 4 steps
1: iron(III) chloride; N-chloro-succinimide / N,N-dimethyl-formamide / 4 h / 50 °C
2: N,N-dimethyl-formamide / 6 h / 100 °C
3: iron; ammonium chloride / ethanol; water / 5 h / Reflux
4: ethanol; water / 2 h / 20 °C
Multi-step reaction with 4 steps
1: iron(III) chloride; N-chloro-succinimide / N,N-dimethyl-formamide / 4 h / 50 °C
2: triethylamine / N,N-dimethyl-formamide / 6 h / 100 °C
3: iron; ammonium chloride / ethanol; water / 5 h / Reflux
4: ethanol; water / 2 h / 20 °C
Multi-step reaction with 3 steps
1: triethylamine / N,N-dimethyl-formamide / 6 h / 100 °C
2: iron; ammonium chloride / ethanol; water / 5 h / Reflux
3: ethanol; water / 2 h / 20 °C
Multi-step reaction with 3 steps
1: N,N-dimethyl-formamide / 6 h / 100 °C
2: iron; ammonium chloride / ethanol; water / 5 h / Reflux
3: ethanol; water / 2 h / 20 °C