EP1515958A2 - Process for the synthesis of mosapride - Google Patents

Process for the synthesis of mosapride

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Publication number
EP1515958A2
EP1515958A2 EP03760090A EP03760090A EP1515958A2 EP 1515958 A2 EP1515958 A2 EP 1515958A2 EP 03760090 A EP03760090 A EP 03760090A EP 03760090 A EP03760090 A EP 03760090A EP 1515958 A2 EP1515958 A2 EP 1515958A2
Authority
EP
European Patent Office
Prior art keywords
formula
compound
base
acid
mosapride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03760090A
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German (de)
French (fr)
Inventor
Krisztina Vukics
János Fischer
Sándor LEVAI
Péter ERDELYI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
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Application filed by Richter Gedeon Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Publication of EP1515958A2 publication Critical patent/EP1515958A2/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a process for the synthesis of a known benzamide derivative of formula (I).
  • This benzamide derivative - known as mosapride citrate, the chemical name: (RjS)-
  • the synthesis can be carried out by two different methods: a) In the first method 2-aminomethyl-4-(4-fluoro-benzyl)-morpholine of formula (VII) is acylated with the active derivative of 4-amino-5-chloro-2-ethoxy-benzoic-acid and the mosapride base of formula (IX) is isolated.
  • the European Pharmacopoeia 2000 mentions the ( ⁇ ) c/s-4-amino-5-chloro- ⁇ /- (2-chloro-(4-((1-(3-(4-fluoro-phenoxy-propyl)-3-methoxy-piperidine-4-yl)-amino-carbonyl)-5- methoxy-phenyl)-2-methoxy-benzamide - the product of an analogue amidation reaction - as a by-product.
  • the mosapride base of formula (IX) can be isolated only in 73% yield by the acetic hydrolysis of ⁇ /-acetyl-mosapride.
  • the object of the invention is to develop a process, which eliminates the disadvantages of the known processes and according to which high quality product can be obtained in good yield by simple technology. Surprisingly it was found by our experiments, that the above difficulties can be solved by using in the peptide chemistry usual /V-tert-butoxy-carbonyl protecting group, on this not peptide chemical field as well.
  • the compound of formula (II) is reacted with di-tert-butyl-dicarbonate in alcohol in the presence of a base.
  • the solvent is preferably ethanol and the base is sodium-hydroxide.
  • the novel compound of formula (III), the chemical name: 4-(4-tert-butoxy-carbonyl-amino)- 2-hydroxy-benzoic-acid can be produced by this method in higher than 90% yield.
  • the obtained compound of formula (III) is reacted with an alkylating agent in an inert solvent in the presence of a base.
  • the compound of formula (IV) is also novel, the chemical name: 4-(t ⁇ / -butoxy- carbonyl-amino)-2-ethoxybenzoate and can be produced practically in quantitative yield by this method.
  • the compound of formula (IV) is hydrolyzed in alcohol with a base, preferably in ethanol with sodium-hydroxide and then the obtained salt is neutralized with an acid, preferably with hydrogen chloride solution.
  • a base preferably in ethanol with sodium-hydroxide
  • an acid preferably with hydrogen chloride solution.
  • novel compound of formula (V) the chemical name: 4-(fert-butoxy- carbonyl-amino)-2-etoxybenzoic acid can be produced by this method in very good, practically quantitative yield.
  • the compound of formula (V) is reacted with a chlorinating agent in an inert solvent, preferably with /V-chloro-succinimide warming in tetrahydrof uran.
  • the intermediate of formula (VI) is more favourable then the known 4-(acetyl-amino)-5-chloro-2-etoxybenzoic acid, namely the selective hydrolysis can be carried out with better yield.
  • the compound of formula (VI) is reacted with 2-(amino-methyl)-4-(4- fluoro-benzyl)-morpholine of formula (VII) in an inert solvent in the presence of a base.
  • activating and coupling reagents from the peptide chemistry are used for carboxylic amide formation, preferably carbodiimide dertivative, mixed anhydride or more preferably triphenylphosphite/imidazole coupling.
  • novel compound of formula (VIM) the chemical name: 4-(terf-butoxy- carbonyl-amino)-5-chloro-2-ethoxy- ⁇ - ⁇ [4-fluoro-benzyl)-2-morpholinyl]-methyl ⁇ -benzamide can be produced by this method in high purity and a very good, 77-92% yield.
  • the carbodiimide coupling is carried out preferably reacting with 1 -ethyl-3-[3- (dimethylamino)-propyl]-carbodiimide hydrochloride in anhydrous dichloromethane.
  • the mixed anhydride coupling is carried out preferably reacting with pivaloyl chloride cooling at -10 S C.
  • triphenyl-phosphite / imidazole reagents are used in excess, preferably in 50% excess in an inert solvent, preferably in dry tetrahydrof urane during heating.
  • the protecting group is removed with an acid from the compound of formula (VIII), which can be carried out preferably by the following methods.
  • the mosapride hydrochloride or trifluoroacetic acid salt can be obtained by these methods, from which the mosapride base of formula (IX) is liberated. Thereafter the pharmaceutically acceptable salt, preferably the citrate dihydrate is produced with an acid, preferably with citric acid.
  • the removal of the 4-(tet -butoxy-carbonyl) protecting group can be carried out preferably with concentrated hydrochloride acid solution and after alkalization the mosapride base of formula (IX) is obtained practically in quantitative yield.
  • mosapride citrate dihydrate of formula (I) is highly pure, so satisfies the strict quality requirement of pharmaceutical active ingredients.
  • novel compounds of formula (III), (IV), (V), (VI) and (VIII) of the synthetic route above are also object of the invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention relates to a process for the synthesis of mosapride citrate of formula (I), the chemical name: (R,S)-4-amino-5-chloro-2-ethoxy-N-{ [4-(4-fluoro-benzyl)-2­ morpholinyl]-methyl}benzamide citrate dihydrate, (I), (II) reacting the compound of formula (II) with di-tert-butyl-dicarbonate in an alcohol in the presence of a base, the obtained product is ethylated in an inert solvent in the presence of a base, the obtained compound is hydrolyzed with an alkyl-hydroxide and the obtained salt neutralized with an acid, the obtained product is chlorinated, and the obtained compound of formula (VI) is reacted with the compound of formula (VII), (VI), (VII) where BOC is tert-butoxy-carbonyl protecting group and removing the protecting group from the obtained compound of formula (VIII) the mosapride base is prepared, (VIII) where BOC is defined as above and in desired case with an acid, preferably with citric acid a pharmaceutically acceptable salt, preferably the mosapride citrate dehydrate of formula (I) is produced.

Description

Process for the synthesis of a benzamide derivative
The invention relates to a process for the synthesis of a known benzamide derivative of formula (I). This benzamide derivative - known as mosapride citrate, the chemical name: (RjS)-
4-amino-5-chloro-2-ethoxy-/V-{[4-(4-fluoro-benzyl)-2-morpholinyl]methyl}benzamide citrate dihydrate - is the active ingredient of a modern gastrointestinal motility enhancing drug.
(1) The synthesis of this compound is described in the HU 198193 (equivalent of EP
243959).
According to this Patent Specification the synthesis can be carried out by two different methods: a) In the first method 2-aminomethyl-4-(4-fluoro-benzyl)-morpholine of formula (VII) is acylated with the active derivative of 4-amino-5-chloro-2-ethoxy-benzoic-acid and the mosapride base of formula (IX) is isolated.
(VII)
(|X)
This method did not use protecting groups on the aromatic amine group, therefore by-products are produced and therefore the mosapride base of formula (IX) can be isolated only in poor yield. b) In the second method the compound of formula (VII) is acylated with the active derivative of 4-acetylamino-5-chloro-2-ethoxy-benzoic-acid. From the obtained product the acetyl protecting group is removed by selective hydrolysis and the mosapride base of formula (IX) is isolated. By the synthesis of the near analogue active ingredient: cisapride also by-products are obtained. The European Pharmacopoeia 2000 mentions the (±) c/s-4-amino-5-chloro-Λ/- (2-chloro-(4-((1-(3-(4-fluoro-phenoxy-propyl)-3-methoxy-piperidine-4-yl)-amino-carbonyl)-5- methoxy-phenyl)-2-methoxy-benzamide - the product of an analogue amidation reaction - as a by-product.
This explains that according to the Patent Specification above the mosapride base of formula (IX) with carbodiimide coupling could be isolated only in 47% yield.
The second method is described also in HU 198193 (equivalent of EP 243959). According to this method this problem was tried to solve by protecting the aromatic amino group with acetyl group.
The by-process mentioned above did not occur in this case and the yield of the cabodiimide coupling reaction increased to 63% calculated on Λ/-acetyl-mosapride base.
The mosapride base of formula (IX) can be isolated only in 73% yield by the acetic hydrolysis of Λ/-acetyl-mosapride.
That means it is difficult to carry out the selective hydrolysis, namely the hydrolysis of the Λ/-acetyl group is followed by partial hydrolysis of amide-bond of the mosapride base.
According to the publication in J. Med. Chem. 1991 , 34, 616-624 the production of the starting material: 4-acetylamino-5-chloro-2-ethoxy-benzoic-acid is also difficult. The 4- amino-5-chloro-2-ethoxy-benzoic-acid is prepared practically in quantitative yield by hydrolysis with triple amount of sodium hydroxide solution at reflux temperature. The selective hydrolysis to 4-acetylamino-5-chloro-2-ethoxy-benzoic-acid needs only a small excess of sodium hydroxide solution and 60 °C, but even in this case the selectively hydrolyzed product can be prepared only in 73% yield.
Summarizing, according to the synthetic processes of the prior art the mosapride base of formula (IX) can be isolated only with several by-products and in poor yield.
The object of the invention is to develop a process, which eliminates the disadvantages of the known processes and according to which high quality product can be obtained in good yield by simple technology. Surprisingly it was found by our experiments, that the above difficulties can be solved by using in the peptide chemistry usual /V-tert-butoxy-carbonyl protecting group, on this not peptide chemical field as well.
The recognition according to our invention is that, the key-intermediate of formula
(VI), the chemical name: (4-terf-butoxy-carbonyl-amino)-2-ethoxy-5-chloro-benzoic acid is a novel compound and
(VI) where BOC is ferc-butoxy-carbonyl protecting group,
can be prepared in excellent yield from the 4-amino-salicylic acid of formula (II) by the following method.
(II)
The compound of formula (II) is reacted with di-tert-butyl-dicarbonate in alcohol in the presence of a base. The solvent is preferably ethanol and the base is sodium-hydroxide. The novel compound of formula (III), the chemical name: 4-(4-tert-butoxy-carbonyl-amino)- 2-hydroxy-benzoic-acid can be produced by this method in higher than 90% yield.
(»') where BOC is defined as above,
The obtained compound of formula (III) is reacted with an alkylating agent in an inert solvent in the presence of a base.
Preferably twice the stoichiometric amount of ethyl-iodide is used warming in dimethyl-formamide. The compound of formula (IV) is also novel, the chemical name: 4-(tø/ -butoxy- carbonyl-amino)-2-ethoxybenzoate and can be produced practically in quantitative yield by this method.
(IV) where BOC is defined as above,
The compound of formula (IV) is hydrolyzed in alcohol with a base, preferably in ethanol with sodium-hydroxide and then the obtained salt is neutralized with an acid, preferably with hydrogen chloride solution. The also novel compound of formula (V), the chemical name: 4-(fert-butoxy- carbonyl-amino)-2-etoxybenzoic acid can be produced by this method in very good, practically quantitative yield.
(V) where BOC is defined as above,
The compound of formula (V) is reacted with a chlorinating agent in an inert solvent, preferably with /V-chloro-succinimide warming in tetrahydrof uran.
The also novel intermediate of formula (VI), the chemical name: 4-(tert-butoxy- carbonyl-amino)-5-chloro-2-etoxybenzoic acid can be produced by this method in higher than 90% yield.
(VI) where BOC is defined as above,
According to our invention the intermediate of formula (VI) is more favourable then the known 4-(acetyl-amino)-5-chloro-2-etoxybenzoic acid, namely the selective hydrolysis can be carried out with better yield. In the next step the compound of formula (VI) is reacted with 2-(amino-methyl)-4-(4- fluoro-benzyl)-morpholine of formula (VII) in an inert solvent in the presence of a base.
(VII)
For this reason activating and coupling reagents from the peptide chemistry are used for carboxylic amide formation, preferably carbodiimide dertivative, mixed anhydride or more preferably triphenylphosphite/imidazole coupling.
The also novel compound of formula (VIM), the chemical name: 4-(terf-butoxy- carbonyl-amino)-5-chloro-2-ethoxy-Λ-{[4-fluoro-benzyl)-2-morpholinyl]-methyl}-benzamide can be produced by this method in high purity and a very good, 77-92% yield.
(VIII) where BOC is defined as above,
The carbodiimide coupling is carried out preferably reacting with 1 -ethyl-3-[3- (dimethylamino)-propyl]-carbodiimide hydrochloride in anhydrous dichloromethane.
The mixed anhydride coupling is carried out preferably reacting with pivaloyl chloride cooling at -10 SC.
The triphenyl-phosphite / imidazole reagents are used in excess, preferably in 50% excess in an inert solvent, preferably in dry tetrahydrof urane during heating.
Then the protecting group is removed with an acid from the compound of formula (VIII), which can be carried out preferably by the following methods.
a.) hydrochloric acid / ethylacetate b.) trifluoroacetic acid c.) concentrated hydrochloric acid solution
The mosapride hydrochloride or trifluoroacetic acid salt can be obtained by these methods, from which the mosapride base of formula (IX) is liberated. Thereafter the pharmaceutically acceptable salt, preferably the citrate dihydrate is produced with an acid, preferably with citric acid.
The removal of the 4-(tet -butoxy-carbonyl) protecting group can be carried out preferably with concentrated hydrochloride acid solution and after alkalization the mosapride base of formula (IX) is obtained practically in quantitative yield.
The advantages of the process according to the invention can be summarized as follows: according to the process described in HU 198193 (equivalent of EP 243959) the mosapride base of formula (IX) can be obtained only in 65-75% yield, but using the new process of the invention the yield is above 90%.
The advantage of this process is that the obtained mosapride citrate dihydrate of formula (I) is highly pure, so satisfies the strict quality requirement of pharmaceutical active ingredients.
The novel compounds of formula (III), (IV), (V), (VI) and (VIII) of the synthetic route above are also object of the invention.
The invention is illustrated by the following not limiting Examples:
Example 1 Synthesis of 4-(terf-butoxy-carbonyl)-2-hydroxy-benzoic acid (III)
To the suspension of 15.31 g (0.1 mol) of 4-amino-salicylic acid (II) and 153 ml of ethanol 8.0 g (0.2 mol) of sodium-hydroxide in 108 ml of water is added at 5 -10 °C. To the obtained solution 43.65 g (0.2 mol) of di-tetf-butyl-dicarbonate in 63 ml of ethanol is added dropwise at the same temperature in 1 hour. The reaction mixture is allowed to warm to room temperature and stirred for 24 hours, then cooled to 5 -10 °C and 240 ml of 1 M aqueous hydrochloric acid solution and 84 ml of water added dropwise. The precipitated product is filtered, washed with 50 ml of 1 M aqueous hydrochloric acid solution and 3x50 ml of water, to give 23.18 g (92%) of the title compound. Mp: 176-177 °C. 1H NMR (DMSO, 30°C): δ (ppm) = 1.49 s (9H), 7.00 dd (1 H), 7.14 d (1 H), 7.66 d (1 H), 9.69 s (1 H), 2.80-4.50 s,vbr and 10.50-12.10 s,vbr.
Example 2
Synthesis of 4-(fert-butoxy-carbonyl-amino)-2-ethoxy-benzoate (IV) 10.12 g (0.04 mol) of compound (III), 13.8 g (0.1 mol) of potassium carbonate, 100 ml of /V,Λ/-dimethyl-formamide and 8.0 ml (0.1 mol) of ethyl-iodide are stirred at 60 °C for 6 hours. The solvent is evaporated under reduced pressure and 100 ml of water added to the residue. The obtained product is filtered, washed with water, to give 11.99 g (97%) of the title compound. Mp: 116-118 °C.
1H NMR (DMSO, 30°C): δ (ppm) = 1.27 t (3H), 1.34 t (3H), 1.48 s (9H), 4.00 q (2H), 4.20 q (2H), 7.05 dd (1 H), 7.32 d (1 H), 7.60 d (1 H), 9.62 s (1 H).
Example 3 Synthesis of 4-(tert-butoxy-carbonyl-amino)-2-ethoxy-benzoic acid (V)
12.36 g (0.04 mol) of compound (III) is solved in 80 ml of ethanol and 4.0 g (0.1 mol) of sodium hydroxide solution in 104 ml of water added. The white suspension is stirred at 60 °C for 6 hours, while the sodium salt of the obtaining product solved. The reaction mixture is cooled to 0°C and 120 ml (0.12 mol) of 1 M hydrochloric acid added dropwise. The precipitated product is filtered, washed with water, to give 10.9 g (97%) of the title compound. Mp: 186-187 °C
1H NMR (DMSO, 30°C): δ (ppm) = 1.34 t (3H), 1.48 s (9H), 4.02 q (1 H), 7.03 dd (1 H), 7.32 d (1 H), 7.61 d (1 H), 9.60 s (1 H), 11.90-12.20 s,br (1 H).
Example 4
Synthesis of 4-(terf-butoxy-carbonyl-amino)-5-chloro-2-ethoxy-benzoic acid (VI)
9.83 g (0.035 mol) of compound (V) and 5.14 g (0.039 mol) of /V-chloro-succinimide are stirred in 59 ml of tetrahydrofuran for 6 hours. The solvent is evaporated under reduced pressure. To the residue 70 ml of dichloromethane is added and extracted with 3 x 1 M aqueous sodium hydroxide solution. The combined aqueous phases are cooled to 0 °C and acidified with 3 M hydrochloric acid solution. The precipitated product is filtered, washed with water to give 10.27 g (93%) of the title compound.
Mp: 152-153°C. 1H NMR (DMSO, 30°C): δ (ppm) = 1.341 (3H), 1.48 s (9H), 4.07 q (1 H), 7.57 s (1 H), 7.68 S
(1 H), 8.59 s (1 H), 12.30-13.00 s,vbr (1 H).
Example 5
Synthesis of (f?,S)-4-(ter -butoxy-carbonyl-amino)-5-chloro-2-ethoxy- ^{[4-(4- fluoro-benzyl)-2-morpholinyl]methyi}-benzamide (VIII) A.)
5.61 g (0.025 mol) of compound (VII), 7.89 g (0.025 mol) of compound (VI), 2.55 g (0.0375 mol) of imidazole and 9.83 ml (0.0375 mol) of triphenyl phosphite are stirred in 31 ml of tetrahydrofuran at 60 °C for 7 hours. The solvent is evaporated under reduced pressure. The residue oil is extracted with 100 ml of dichloromethane and 75 ml of water. The pure phases are separated, the aqueous phase is extracted with 50 ml of dichloromethane and the combined organic phases with 2x50 ml of water. The organic phase is dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure. To the residue 75 ml of diisopropyl-ether is added, the product crystallized from the obtained solution in stirring filtered and washed with water to give 12.0 g (92 %) of the title compound. Mp: 158-160 °C.
1H NMR (DMSO, 30°C): δ (ppm) = 1.39 t (3H), 1.48 s (9H), 1.89 dd (1 H), 2.08 ddd (1 H), 2.56-2.64 m (1 H), 2.69-2.77 m (1 H), 3.22-3.30 m (1 H), 3.37-3.43 m (1 H), 3.46 S (2H), 3.48- 3.64 m (2H), 3.78-3.86 m (1 H), 4.13 q (2H), 7.09-7.18 m (2H), 7.29-7.37 m (2H), 7.58 s (1 H), 7.81 s (1 H), 8.22 1 (1 H), 8.62 s (1 H). B.)
0.67 g (3 mmol) of compound (VII), 0.95 g (3 mmol) of compound (VI) and 0.63 g (3.3 mmol) of 1-(diethyl-amino-propyl)-3-ethyl-carbodiimide-hydrochloride are stirred in 12 ml of anhydrous dichloromethane at room temperature for 5 hours. To the reaction mixture 10% aqueous sodium-carbonate solution is added, the phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure. To the residue oil 1 M aqueous hydrochloric acid solution is added, the precipitated hydrochloride salt filtered, washed with water to give 1.29 g (77 %) of the title compound. Mp: 220-225 °C.
C)
The mixture of 0.95 g (3 mmol) of compound (VI), 0.48 ml (3.45 mmol) of triethylamine and 5 ml of anhydrous dichloromethane is cooled to -10 °C and 0.41 ml (3.3 mmol) of pivaloyl chloride added dropwise with stirring. The obtained suspension is stirred at -10 °C for 30 minutes and then 0.67 g (3 mmol) of compound (VII) added in 5 ml of anhydrous dichloromethane. The mixture is stirred at 0 °C for 2 hours and at room temperature during the night. The reaction mixture is treated substantially the same manner as in Example B) to give 1.31 g (78%) hydrochloride salt of the title compound.
Example 6
Synthesis of (/?,SH-amino-5-chloro-2-ethoxy-ΛK[4-(4-fluoro-benzyl)-2- morpholinyl]-methyl}-benzamide citrate dyhidrate (mosapride citrate dyhidrate) (I) A.) 1.04 g (2 mmol) of compound (VIII) and 15 ml 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.
B.)
The solution of 1.04 g (2 mmol) of compound (VIII), 13 ml of dichloromethane and 0.77 ml 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: 186-193°C.
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: 110-113°C.
C)
To the suspension of 1.3 g (2.5 mmol) of compound (VIII) and 3 ml of water 12 m of I 37% aqueous hydrochloric acid solution is added. The obtained solution is stirred at 40 °C for 3 hours, cooled to 10 °C and 38 ml 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: 110-113°C.
Example 7
Synthesis of 2-aminomethyl-4-(4-fluoro-benzyl) morpholine (VII) A.)
16.2 g (265 mmol) of 2-amino-ethanol, 27.3 g (220 mmol) of 4-fluoro-benzaldehyde and 27.6 g of sodium-hydrogen-carbonate are refluxed in 260 ml of methanol with stirring for 4 hours and then 5.00 g (132 mmol) of sodium-borohydride is added at 0-5 °C for 2 hours. The reaction mixture is allowed to warm to room temperature, after the evolution of hydrogen is stopped filtered and evaporated under reduced pressure. The residue is solved in dichloromethane, washed 2 x with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 32.8 g (88%) of 2-(4- fluoro-benzyl-amino)-ethanol as colourless, viscous oil.
B) To 15.0 g (88.7 mmol) of 2-(4-fluoro-benzyl-amino)-ethanol obtained in the above (A) step 8.65 g (92.5 mmol) of epichlorohydrin is added, the mixture stirred 4.5 hours, 66 g of concentrated sulphuric acid added during 15 minutes and warmed at 150 °C for 30 minutes. After cooling the sulphuric acid solution is poured into ice/water, treated with saturated sodium hydroxide solution and extracted with chloroform. The extract is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated under reduced pressure, to give 16.1 g (75%) of 2-chloro-methyl-4-(4-fluoro-benzyl)- morpholine as yellow, viscous oil.
C) 12.3 g (50.5 mmol) of 2-chloro-methyl-4-(4-fluoro-benzyl)-morpholine obtained in the above (B) step is solved in 195 ml of anhydrous /V,/V-dimethyl-formamide and 10.6 g (57.2 mmol) of potassium-phthalimide added to the solution. The suspension is refluxed for 1.5 hours, then cooled and filtered. The solvent is evaporated under reduced pressure, the residue solved in chloroform and washed with water four times, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is recrystallized from isopropanol to give 13.5 g (75%) of nearly white 2-[4-(4-fluoro-benzyl)-morpholine-2yl-methyl]-isoindole- 1.3-dion crystals. Mp: 150-151 °C.
D)
10.0 g (28.1 mmol) of 2-[4-(4-fluoro-benzyl)-morpholine-2yl-methyl]-isoindole-1.3-dion obtained in the above (C) step is suspended in the solution of 5.32 g (106 mmol) of hydrazine-monohydrate and 170 ml of ethanol and refluxed for 3 hours. The precipitation is removed by filtration and the ethanol solvent is evaporated under reduced pressure. The residue is solved in water and the solution extracted with dichloromethane. The organic phase is washed 2 x with water, dried over sodium sulphate, filtered and evaporated under reduced pressure, to give 5.67 g (90%) of the title compound as yellow transparent oil.

Claims

CLAIMS:
1.) Process for the synthesis of mosapride citrate of formula (I), the chemical name: ( :?,S)-4-amino-5-chloro-2-ethoxy-/V-{[4-(4-fluoro-benzyl)-2-morpholinyl]-methyl}- benzamide citrate dihydrate
(I) characterized by reacting 4-aminosalicylic acid of formula (II) with di-tetf-butyl- dicarbonate in alcohol in the presence of a base,
(II) the obtained compound of formula (III) is reacted with an alkylating agent in an inert solvent in the presence of a base,
(III) where BOC is a tert-butoxy-carbonyl* protecting group,
the obtained compound of formula (IV) is hydrolyzed in an alcohol with a base and the obtained salt neutralized with an acid,
(IV) where BOC is defined as above the obtained compound of formula (V) is reacted with a chlorinating agent in an inert solvent,
(V) where BOC is defined as above the obtained compound of formula (VI) is reacted with 2-aminomethyl-4-(4-fluoro- benzyl)-morpholine of formula (VII) in an inert solvent in the presence of a base,
(VI) where BOC is defined as above
(VII) removing the protecting group from the compound of formula (VII) the mosapride base of formula (IX) is isolated,
(VIII) where BOC is defined as above
(IX) in a desired case with an acid, preferably with citric acid a pharmaceutically acceptable salt, preferably the citrate dehydrate of formula (I) is prepared
2.) The process according to claim 1 , characterized by using preferably ethyl iodide as ethylating agent.
3.) The process according to claim 1 , characterized by using preferably Λ/-chloro- succinimide as a chlorinating agent.
4.) The compound of formula (III)
(III)
5.) The compound of formula (IV)
(IV)
6.) The compound of formula (V)
(V)
7.) The compound of formula (VI)
(VI)
8.) The compound of formula (VIII)
EP03760090A 2002-06-13 2003-06-12 Process for the synthesis of mosapride Withdrawn EP1515958A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HU0201980A HUP0201980A3 (en) 2002-06-13 2002-06-13 Process for preparing a benzamide derivative and intermediates thereof
HU0201980 2002-06-13
PCT/HU2003/000042 WO2003106440A2 (en) 2002-06-13 2003-06-12 Process for the synthesis of a benzamide derivative

Publications (1)

Publication Number Publication Date
EP1515958A2 true EP1515958A2 (en) 2005-03-23

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WO (1) WO2003106440A2 (en)

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Publication number Priority date Publication date Assignee Title
KR100750593B1 (en) * 2006-03-16 2007-08-20 동우신테크 주식회사 Process for preparing substituted benzamide derivatives
JP2008247753A (en) * 2007-03-29 2008-10-16 Dainippon Sumitomo Pharma Co Ltd Method for producing 4-amino-5-chloro-2-ethoxy-n-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide
KR100986734B1 (en) * 2008-03-21 2010-10-13 하나제약 주식회사 Novel Synthetic Method of Intermediate for Mosapride
WO2011107903A1 (en) 2010-03-04 2011-09-09 Ranbaxy Laboratories Limited Highly pure mosapride citrate dihydrate and processes for its preparation
CN105301118B (en) * 2014-07-02 2018-05-25 成都康弘药业集团股份有限公司 A kind of detection method of mosapride citrate in relation to substance
KR102275045B1 (en) * 2019-02-13 2021-07-08 한국바이오켐제약 주식회사 Methods for preparing mosapride citrate hydrate and pharmaceutical composition comprising the same

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US4870074A (en) * 1986-04-30 1989-09-26 Dainippon Pharmaceutical Co., Ltd. Substituted benzamide derivatives, for enhancing gastrointestinal motility
TW213460B (en) * 1991-02-15 1993-09-21 Hokuriku Pharmaceutical
US5783593A (en) * 1993-11-04 1998-07-21 Abbott Laboratories Inhibitors of squalene synthetase and protein farnesyltransferase

Non-Patent Citations (1)

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Title
See references of WO03106440A3 *

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HUP0201980A2 (en) 2004-03-01
WO2003106440A2 (en) 2003-12-24
AU2003242867A8 (en) 2003-12-31
AU2003242867A1 (en) 2003-12-31
WO2003106440A3 (en) 2004-06-17
HUP0201980A3 (en) 2008-06-30
HU0201980D0 (en) 2002-08-28

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