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.

Landscapes

• 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)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (2)

Family

ID=89980512

Family Applications (1)

Country Status (4)

Cited By (7)

Family Cites Families (3)

• 2002
  • 2002-06-13 HU HU0201980A patent/HUP0201980A3/hu unknown
• 2003
  • 2003-06-12 EP EP03760090A patent/EP1515958A2/en not_active Withdrawn
  • 2003-06-12 WO PCT/HU2003/000042 patent/WO2003106440A2/en not_active Application Discontinuation
  • 2003-06-12 AU AU2003242867A patent/AU2003242867A1/en not_active Abandoned

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