EP1515958A2 - Process for the synthesis of mosapride - Google Patents
Process for the synthesis of mosaprideInfo
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- 229960004085 mosapride Drugs 0.000 title claims abstract description 27
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000012442 inert solvent Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract 2
- JHSPPBBJOLKJDH-UHFFFAOYSA-N [4-[(4-fluorophenyl)methyl]morpholin-2-yl]methanamine Chemical compound C1COC(CN)CN1CC1=CC=C(F)C=C1 JHSPPBBJOLKJDH-UHFFFAOYSA-N 0.000 claims description 10
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims description 7
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 3
- 229960004909 aminosalicylic acid Drugs 0.000 claims description 3
- 239000012320 chlorinating reagent Substances 0.000 claims description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000012021 ethylating agents Substances 0.000 claims 1
- LRZSAGKIMYFLHY-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;dihydrate Chemical compound O.O.OC(=O)CC(O)(C(O)=O)CC(O)=O LRZSAGKIMYFLHY-UHFFFAOYSA-N 0.000 abstract description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 abstract description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- 229940083608 sodium hydroxide Drugs 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ICNWZXFWTBMBKT-UHFFFAOYSA-N 4-acetamido-5-chloro-2-ethoxybenzoic acid Chemical class CCOC1=CC(NC(C)=O)=C(Cl)C=C1C(O)=O ICNWZXFWTBMBKT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- KWEPMOQQKUYWIN-UHFFFAOYSA-N 2-[(4-fluorophenyl)methylamino]ethanol Chemical compound OCCNCC1=CC=C(F)C=C1 KWEPMOQQKUYWIN-UHFFFAOYSA-N 0.000 description 2
- HEWZYIAVDJRALA-UHFFFAOYSA-N 2-[[4-[(4-fluorophenyl)methyl]morpholin-2-yl]methyl]isoindole-1,3-dione Chemical compound C1=CC(F)=CC=C1CN1CC(CN2C(C3=CC=CC=C3C2=O)=O)OCC1 HEWZYIAVDJRALA-UHFFFAOYSA-N 0.000 description 2
- BHYLGLXUBUSYTE-UHFFFAOYSA-N 2-chloro-4-[(4-fluorophenyl)methyl]-2-methylmorpholine Chemical compound C1COC(C)(Cl)CN1CC1=CC=C(F)C=C1 BHYLGLXUBUSYTE-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- XWGYOMHQGQZRLC-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxybenzoic acid Chemical class CCOC1=CC(N)=C(Cl)C=C1C(O)=O XWGYOMHQGQZRLC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 150000003936 benzamides Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- CDPDMSRMABBUEV-UHFFFAOYSA-N 2-ethoxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]benzoic acid Chemical compound CCOC1=CC(NC(=O)OC(C)(C)C)=CC=C1C(O)=O CDPDMSRMABBUEV-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- YBQHKPAIKGWCQH-UHFFFAOYSA-N 3-ethyl-1-(ethyliminomethylideneamino)pentan-3-amine;hydrochloride Chemical compound Cl.CCN=C=NCCC(N)(CC)CC YBQHKPAIKGWCQH-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000004982 aromatic amines Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- -1 sodium-borohydride Chemical compound 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0201980 | 2002-06-13 | ||
| HU0201980A HUP0201980A3 (en) | 2002-06-13 | 2002-06-13 | Process for preparing a benzamide derivative and intermediates thereof |
| 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 |
Family
ID=89980512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP03760090A Withdrawn EP1515958A2 (en) | 2002-06-13 | 2003-06-12 | Process for the synthesis of mosapride |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1515958A2 (hu) |
| AU (1) | AU2003242867A1 (hu) |
| HU (1) | HUP0201980A3 (hu) |
| WO (1) | WO2003106440A2 (hu) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100750593B1 (ko) * | 2006-03-16 | 2007-08-20 | 동우신테크 주식회사 | 치환된 벤즈아미드 유도체의 제조방법 |
| JP2008247753A (ja) * | 2007-03-29 | 2008-10-16 | Dainippon Sumitomo Pharma Co Ltd | ４−アミノ−５−クロロ−２−エトキシ−ｎ−［［４−（４−フルオロベンジル）−２−モルホリニル］メチル］ベンズアミドの製造方法 |
| KR100986734B1 (ko) * | 2008-03-21 | 2010-10-13 | 하나제약 주식회사 | 모사프리드 제조용 중간체의 제조방법 |
| WO2011107903A1 (en) | 2010-03-04 | 2011-09-09 | Ranbaxy Laboratories Limited | Highly pure mosapride citrate dihydrate and processes for its preparation |
| CN105301118B (zh) * | 2014-07-02 | 2018-05-25 | 成都康弘药业集团股份有限公司 | 一种枸橼酸莫沙必利有关物质的检测方法 |
| KR102275045B1 (ko) * | 2019-02-13 | 2021-07-08 | 한국바이오켐제약 주식회사 | 모사프리드시트르산염수화물의 제조방법 및 이를 포함하는 약학제제 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ284687B6 (cs) * | 1986-04-30 | 1999-02-17 | Dainippon Pharmaceutical Co., Ltd. | Substituovaný benzamidový derivát, způsob jeho výroby a farmaceutický prostředek na jeho bázi |
| TW213460B (hu) * | 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 |
-
2002
- 2002-06-13 HU HU0201980A patent/HUP0201980A3/hu unknown
-
2003
- 2003-06-12 AU AU2003242867A patent/AU2003242867A1/en not_active Abandoned
- 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
Non-Patent Citations (1)
| Title |
|---|
| See references of WO03106440A3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0201980A3 (en) | 2008-06-30 |
| AU2003242867A8 (en) | 2003-12-31 |
| WO2003106440A2 (en) | 2003-12-24 |
| HU0201980D0 (hu) | 2002-08-28 |
| AU2003242867A1 (en) | 2003-12-31 |
| WO2003106440A3 (en) | 2004-06-17 |
| HUP0201980A2 (hu) | 2004-03-01 |
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