NO172287B - PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -ACETIC ACID AND ITS DIHYDROCHLORIDE - Google Patents
PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -ACETIC ACID AND ITS DIHYDROCHLORIDE Download PDFInfo
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- NO172287B NO172287B NO894650A NO894650A NO172287B NO 172287 B NO172287 B NO 172287B NO 894650 A NO894650 A NO 894650A NO 894650 A NO894650 A NO 894650A NO 172287 B NO172287 B NO 172287B
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- Prior art keywords
- phenylmethyl
- piperazinyl
- chlorophenyl
- alkali metal
- dihydrochloride
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- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title description 2
- ZJQSBXXYLQGZBR-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethanol Chemical compound C1CN(CCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZJQSBXXYLQGZBR-UHFFFAOYSA-N 0.000 claims description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- -1 alkali metal halide acetate Chemical class 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- 150000001340 alkali metals Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 claims description 5
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 claims description 5
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000003247 decreasing effect Effects 0.000 claims 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PGLIUCLTXOYQMV-UHFFFAOYSA-N Cetirizine hydrochloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 229960001803 cetirizine Drugs 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- ALKWTKGPKKAZMN-UHFFFAOYSA-N 1-chloro-4-[chloro(phenyl)methyl]benzene Chemical compound C=1C=C(Cl)C=CC=1C(Cl)C1=CC=CC=C1 ALKWTKGPKKAZMN-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960004342 cetirizine hydrochloride Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 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
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000036997 mental performance Effects 0.000 description 1
- RDFIZBYHUOHTQI-UHFFFAOYSA-N methyl 2-(2-chloroethoxy)acetate Chemical compound COC(=O)COCCCl RDFIZBYHUOHTQI-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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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)
Description
Den foreliggende oppfinnelse angår en ny fremgangsmåte for fremstilling av 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre og dens dihydroklorid. The present invention relates to a new process for the production of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid and its dihydrochloride.
Dihydrokloridet av 2-[2-[4-[(4-klorfenyl)-fenyl-methyl] -1-piperazinyl] -ethoxy] -eddiksyre, som også er kjent under trivialnavnet cetirizin, er nylig blitt innført som et nytt medikament for behandling av allergiske syndromer, som f.eks. kronisk og akutt allergisk rhinitis, allergisk con-junctivitis, pruritus, urticaria, osv. Ved anvendelse i tera-pien har denne forbindelse vist seg å være bemerkelsesverdig fri for bivirkninger på sentralnervesystemet, som f.eks. døsighet, nedsatt mental ytelsesevne, osv. (se D.P. Tashkin et al., Annals of Allergy, Part II, 59, (1987), 49-52 og F.M. Gengo et al., Annals of Allergy, Part II, 59, (1987), 53-57). The dihydrochloride of 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid, which is also known by the common name cetirizine, has recently been introduced as a new drug for the treatment of allergic syndromes, such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria, etc. When used in therapy, this compound has been shown to be remarkably free of side effects on the central nervous system, such as e.g. drowsiness, impaired mental performance, etc. (see D.P. Tashkin et al., Annals of Allergy, Part II, 59, (1987), 49-52 and F.M. Gengo et al., Annals of Allergy, Part II, 59, (1987 ), 53-57).
I europeisk patentskrift nr. 58 146 beskrives en syntese for fremstilling av 2-[2-[4-[(4-klorfenyl)-fenylm-ethyl] -1-piperazinyl]-ethoxy]-eddiksyre og dens dihydroklorid. I denne syntese er utgangsmaterialet 1-[(4-klorfenyl)-fenyl-methyl ] -piperazin, og dette omsettes med methyl-(2-klor-ethoxy)-acetat, hvorved det fåes methyl-2-[2-[4-[(4-klor-fenyl)-fenylmethyl]-1-piperazinyl]-ethoxy-acetat i et utbytte på 27,8%. Denne methylester underkastes så hydrolyse med en uorganisk base (kalium- eller natriumhydroxyd), hvorved natrium- eller kaliumsaltet fåes, hvilket lett overføres til den frie syre, som så overføres til cetirizindihydroklorid. European patent document no. 58 146 describes a synthesis for the production of 2-[2-[4-[(4-chlorophenyl)-phenylm-ethyl]-1-piperazinyl]-ethoxy]-acetic acid and its dihydrochloride. In this synthesis, the starting material is 1-[(4-chlorophenyl)-phenyl-methyl]-piperazine, and this is reacted with methyl-(2-chloro-ethoxy)-acetate, whereby methyl-2-[2-[4- [(4-chloro-phenyl)-phenylmethyl]-1-piperazinyl]-ethoxy-acetate in a yield of 27.8%. This methyl ester is then subjected to hydrolysis with an inorganic base (potassium or sodium hydroxide), whereby the sodium or potassium salt is obtained, which is easily transferred to the free acid, which is then transferred to cetirizine dihydrochloride.
Den største ulempe ved denne syntese består deri at det totale utbytte av 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-l-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid er på bare 10,6%, beregnet på den benyttede mengde 1-[(4-klorfenyl)-fenyl-methyl ]-1-piperazin. The biggest disadvantage of this synthesis is that the total yield of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride is only 10.6%, calculated on the amount of 1-[(4-chlorophenyl)-phenyl-methyl]-1-piperazine used.
Det har nu lykkes å finne frem til en ny fremgangsmåte som muliggjør fremstilling av 2-[2-[4-[(4-klor-fenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre og dens dihydroklorid i bedre utbytte enn tidligere. It has now succeeded in finding a new method which enables the production of 2-[2-[4-[(4-chloro-phenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid and its dihydrochloride in better yield than previously.
Med oppfinnelsen tilveiebringes det således en fremgangsmåte for fremstilling av 2-[2-[4-[(4-klorfenyl)-fenyl-methyl]-1-piperazinyl]-ethoxy]-eddiksyre med formelen: The invention thus provides a method for the production of 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid with the formula:
og dens dihydroklorid, hvilken fremgangsmåte er karakteristisk ved at 1-[(4-klorfenyl)-fenylmethyl]-piperazin omsettes med 2-klorethanol, og den oppnådde 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethanol med formelen: omsettes med et alkalimetallhalogenacetat med formelen: hvor X er et halogenatom og Me er et alkalimetall, i nærvær av et alkalimetallalkoholat, og at det oppnådde alkalimetallsalt med formelen: hvor Me er som ovenfor angitt, overføres til den tilsvarende syre, som, når nødvendig, overføres til dihydrokloridet. 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl )-ethanolen som fås som et mellomprodukt ved fremgangsmåten ifølge oppfinnelsen, er en kjent forbindelse. Dens fremstilling ved omsetning av 1-piperazinethanol med (4-klorfenyl)-fenylmethylklorid er beskrevet i US patentskrift nr. 2 899 436. Forbindelsen fås ved fremgangsmåten ifølge oppfin nelsen i et høyere utbytte (90%) ved omsetning av 1-[(4-klor-fenyl ) -f enylmethyl] -1-piperazin med 2-klorethanol. Reaksjonen utføres i nærvær av en syreakseptor, som f.eks. en uorganisk base (f.eks. natrium- eller kaliumcarbonat) eller en tertiær organisk base (f.eks. triethylamin), i et inert oppløsnings-middel, som f.eks. toluen, xylen eller annet aromatisk oppløs-ningsmiddel. and its dihydrochloride, which method is characterized in that 1-[(4-chlorophenyl)-phenylmethyl]-piperazine is reacted with 2-chloroethanol, and the obtained 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl ]-ethanol of the formula: is reacted with an alkali metal halide acetate of the formula: where X is a halogen atom and Me is an alkali metal, in the presence of an alkali metal alcoholate, and that the resulting alkali metal salt of the formula: where Me is as indicated above, is transferred to the corresponding acid , which, when necessary, is transferred to the dihydrochloride. The 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl)-ethanol, which is obtained as an intermediate product in the process according to the invention, is a known compound. Its production by reaction of 1-piperazineethanol with (4-chlorophenyl)-phenylmethyl chloride is described in US patent no. 2 899 436. The compound is obtained by the method according to the invention in a higher yield (90%) by reaction of 1-[(4 -chloro-phenyl)-phenylmethyl]-1-piperazine with 2-chloroethanol. The reaction is carried out in the presence of an acid acceptor, such as an inorganic base (e.g. sodium or potassium carbonate) or a tertiary organic base (e.g. triethylamine), in an inert solvent, such as e.g. toluene, xylene or other aromatic solvent.
2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyren fås så ved omsetning av 2-[4-[(4-klor-fenyl ) -f enylmethyl] -1-piperazinyl] -ethanol med et alkalimetallhalogenacetat, som f.eks. natriumkloracetat. Denne reaksjon utføres vanligvis ved at reaktantene oppvarmes ved en temperatur mellom 60 og 100°C i flere timer i nærvær av et alkalimetallalkoholat, som f.eks. kalium-tert-butoxyd, og i et organisk oppløsningsmiddel, fortrinnsvis en alifatisk alkohol med lav reaktivitet, som f.eks. tert-butanol. The 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid is then obtained by reacting 2-[4-[(4-chloro-phenyl)-phenylmethyl]- 1-piperazinyl]-ethanol with an alkali metal halide acetate, such as e.g. sodium chloroacetate. This reaction is usually carried out by heating the reactants at a temperature between 60 and 100°C for several hours in the presence of an alkali metal alcoholate, such as e.g. potassium tert-butoxide, and in an organic solvent, preferably an aliphatic alcohol with low reactivity, such as e.g. tert-butanol.
For å oppnå optimale utbytter er det tilrådelig å benytte kalium-tert-butoxyd og tert-butanol og å etterfylle reaksjonsmediet regelmessig med de to reaktanter (alkalimetallalkoholat og alkalimetallhalogenacetat) i mindre og mindre mengder og med regelmessige mellomrom, inntil reaksjonen er så fullstendig som mulig. To obtain optimal yields, it is advisable to use potassium tert-butoxide and tert-butanol and to replenish the reaction medium regularly with the two reactants (alkali metal alcoholate and alkali metal halide acetate) in smaller and smaller amounts and at regular intervals, until the reaction is as complete as possible .
Eksempelvis kan hver reaktant settes til reaksjonsblandingen hver halvtime i tilsammen fire timer. Hver av de totale molare mengder av alkoholat og halogenacetat som benyt-tes, er med fordel fra 25 til 75% høyere enn den molare mengde av 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethanolen. For example, each reactant can be added to the reaction mixture every half hour for a total of four hours. Each of the total molar amounts of alcoholate and haloacetate used is advantageously from 25 to 75% higher than the molar amount of 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethanol .
Av økonomiske grunner vil det være av interesse å gjenvinne og resirkulere den som utgangsmateriale benyttede alkohol. For dette formål blir oppløsningsmidlet fjernet fra reaksjonsmediet og det sistnevnte tatt opp i surgjort vann (for å bringe pH-verdien på en svakt basisk verdi), hvoretter den som utgangsmateriale benyttede alkohol ekstraheres med diethylether. 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-pipera-zinyl] -ethoxy] -eddiksyren som dannes i løpet av reaksjonen, er tilstede i reaksjonsblandingen i form av et alkalimetallsalt. Etter surgjøring av reaksjonsblandingen til pH 5 ved tilsetning av en uorganisk syre (som f.eks. saltsyre) kan den tilsvarende syre utvinnes fra reaksjonsblandingen ved ekstraksjon med et organisk oppløsningsmiddel (diklormethan, toluen, osv.). Den ønskede syre kan også isoleres i form av godt utkrystalliserte salter. Syren kan overføres til det tilsvarende dihydroklorid på i og for seg konvensjonell måte. For economic reasons, it will be of interest to recover and recycle the alcohol used as starting material. For this purpose, the solvent is removed from the reaction medium and the latter taken up in acidified water (to bring the pH to a slightly basic value), after which the alcohol used as starting material is extracted with diethyl ether. The 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid formed during the reaction is present in the reaction mixture in the form of an alkali metal salt. After acidifying the reaction mixture to pH 5 by adding an inorganic acid (such as hydrochloric acid), the corresponding acid can be recovered from the reaction mixture by extraction with an organic solvent (dichloromethane, toluene, etc.). The desired acid can also be isolated in the form of well-crystallized salts. The acid can be transferred to the corresponding dihydrochloride in a per se conventional manner.
Den nye syntese gir cetirizinhydroklorid i utbytter på 44% eller mer, beregnet på basis av det benyttede l-[(4-klorfenyl)-fenylmethyl]-1-piperazin. Med resirkulering av 2-[4-[ ( 4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethanol til reaksjonsblandingen kan det totale utbytte sogar nå opp i verdier nær 50%. Dette høyere utbytte som oppnås når det startes med l-[(4-klorfenyl)-fenylmethyl]-1-piperazin, representerer et betydelig teknisk fremskritt i forhold til fremgangsmåten beskrevet i europeisk patentskrift nr. 58 146. The new synthesis gives cetirizine hydrochloride in yields of 44% or more, calculated on the basis of the 1-[(4-chlorophenyl)-phenylmethyl]-1-piperazine used. With recycling of 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethanol to the reaction mixture, the total yield can even reach values close to 50%. This higher yield obtained when starting with l-[(4-chlorophenyl)-phenylmethyl]-1-piperazine represents a significant technical advance compared to the process described in European Patent Document No. 58,146.
Det følgende eksempel illustrerer oppfinnelsen. The following example illustrates the invention.
Eksempel Example
Fremstilling av 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-l-pipera-zinyl]-ethoxy]-eddiksyre 1. 2- T4- f( 4- klorfenyl)- fenylmethyl]- 1- piperazinyl]- ethanol♦ Preparation of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid 1. 2-T4-f(4-chlorophenyl)-phenylmethyl]-1-piperazinyl ]- ethanol♦
325 ml tørt toluen, 131,2 g (0,458 mol) 1-[(4-klor-fenyl ) -f enylmethyl] -piperazin og 125 ml (0,9 mol) triethylamin innføres i tur og orden i en to-liters tre-halset rundkolbe utstyrt med en mekanisk rører, en kondensator og et termometer. 41,5 g (0,516 mol) 2-klorethanol settes til denne oppløsning, og blandingen bringes til tilbakeløpstemperaturen under omrøring. Etter oppvarmning i seks timer tilsettes ytterligere 20 g (0,248 mol) 2-klorethanol, og kokingen med tilbakeløpskjøling opprettholdes i ytterligere seks timer. Reaksjonsblandingen kjøles og filtreres, og filtratet inndampes under vakuum i en roterende inndamper. Det isoleres derved 146,5 g 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-etha-nol i form av en gul olje i et utbytte på 96,8%. 50 g av den oppnådde alkohol destilleres ved 220°C under redusert trykk (0,0065 mbar) og oppsamles i to separate fraksjoner. Renheten av hver fraksjon måles ved høytrykks væskekromatografering. Den ene fraksjon på 24,5 g har en renhet på 96,6%, mens den andre fraksjon (på 22,2 g) har en renhet på 99,6%. Det oppnås således et utbytte av rent produkt på 90,4%. 325 ml of dry toluene, 131.2 g (0.458 mol) of 1-[(4-chloro-phenyl)-phenylmethyl]-piperazine and 125 ml (0.9 mol) of triethylamine are introduced in turn into a two-liter three -neck round flask equipped with a mechanical stirrer, a condenser and a thermometer. 41.5 g (0.516 mol) of 2-chloroethanol is added to this solution, and the mixture is brought to the reflux temperature with stirring. After heating for six hours, a further 20 g (0.248 mol) of 2-chloroethanol are added, and the refluxing is maintained for a further six hours. The reaction mixture is cooled and filtered, and the filtrate is evaporated under vacuum in a rotary evaporator. 146.5 g of 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethanol are thereby isolated in the form of a yellow oil in a yield of 96.8%. 50 g of the alcohol obtained is distilled at 220°C under reduced pressure (0.0065 mbar) and collected in two separate fractions. The purity of each fraction is measured by high-pressure liquid chromatography. One fraction of 24.5 g has a purity of 96.6%, while the other fraction (of 22.2 g) has a purity of 99.6%. A yield of pure product of 90.4% is thus achieved.
Den således oppnådde alkohol kan identifiseres i form av dihydrokloridet fremstilt fra en ethanolisk oppløsning av gassformig hydrogenklorid. The alcohol thus obtained can be identified in the form of the dihydrochloride prepared from an ethanolic solution of gaseous hydrogen chloride.
Smeltepunkt 222°C. Melting point 222°C.
Analyse for C19H23C1N20- 2HC1 i % Analysis for C19H23C1N20- 2HC1 in %
2. 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre. 50 g (0,15 mol) 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethanol og 225 ml tert-butanol innføres i en tre-halset rundkolbe utstyrt med en mekanisk rører, et termometer, et nitrogeninntak og en kondensator. Blandingen omrøres for-siktig og oppvarmes til 45°C under nitrogenatmosfære, og det tilsettes 21 g kalium-tert-butoxyd. Temperaturen heves til 75-80°C, og blandingen holdes ved denne temperatur. 11 g natriumkloracetat tilsettes deretter til blandingen, idet tidspunktet for denne tilsetning regnes som tid null. Natriumkloracetat og kalium-tert-butoxyd innføres deretter i tur og orden i reaksjonsblandingen, idet temperaturen holdes ved 75-80°C og det foretas omrøring under nitrogenatmosfære, på følgende måte: etter 45 minutter tilsettes 11 g natriumkloracetat. Etter 1,5 timer tilsettes 5,2 g kalium-tert-butoxyd. Etter to timer tilsettes 5,64 g natriumkloracetat. Etter 2,5 timer tilsettes 1,9 g kalium-tert-butoxyd. Etter tre timer tilsettes 1,9 g natriumkloracetat. Etter 3,5 timer tilsettes 0,8 g kalium-tert-butoxyd. Etter fire timer avslut-tes operasjonen ved tilsetning av 1,13 g natriumkloracetat. Det er derved blitt tilsatt totalt 28,92 g (0,25 mol) kalium-tert-butoxyd (97%) og 30,65 g (0,25 mol) natriumkloracetat (95%). Reaktoren omdannes deretter til et destillasjons-apparat, og ca. 150 ml tert-butanol avdestilleres. Det settes så 190 ml vann til reaksjonsblandingen, og avdestilleringen av tert-butanol i form av en azeotrop med vann tillates å pågå, inntil damptemperaturen har nådd 100°C. 2. 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid. 50 g (0.15 mol) of 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethanol and 225 ml of tert-butanol are introduced into a three-necked round flask equipped with a mechanical stirrer, a thermometer , a nitrogen intake and a condenser. The mixture is carefully stirred and heated to 45°C under a nitrogen atmosphere, and 21 g of potassium tert-butoxide are added. The temperature is raised to 75-80°C, and the mixture is kept at this temperature. 11 g of sodium chloroacetate are then added to the mixture, the time of this addition being considered time zero. Sodium chloroacetate and potassium tert-butoxide are then introduced in turn into the reaction mixture, the temperature being kept at 75-80°C and stirring under a nitrogen atmosphere, as follows: after 45 minutes, 11 g of sodium chloroacetate are added. After 1.5 hours, 5.2 g of potassium tert-butoxide are added. After two hours, 5.64 g of sodium chloroacetate are added. After 2.5 hours, 1.9 g of potassium tert-butoxide is added. After three hours, 1.9 g of sodium chloroacetate are added. After 3.5 hours, 0.8 g of potassium tert-butoxide is added. After four hours, the operation is terminated by the addition of 1.13 g of sodium chloroacetate. A total of 28.92 g (0.25 mol) of potassium tert-butoxide (97%) and 30.65 g (0.25 mol) of sodium chloroacetate (95%) have thereby been added. The reactor is then converted into a distillation apparatus, and approx. 150 ml of tert-butanol is distilled off. 190 ml of water are then added to the reaction mixture, and the distillation of tert-butanol in the form of an azeotrope with water is allowed to continue, until the steam temperature has reached 100°C.
Reaksjonsblandingen avkjøles, fortynnes med 60 ml vann og bringes til pH 8 ved tilsetning av ca. 8 ml konsen- trert saltsyre. De deler av 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethanolen som ikke har reagert, ekstraheres så omhyggelig med diethylether, hvilket muliggjør gjenvinning av 7,3 g etter avdampning av oppløsningsmidlet. The reaction mixture is cooled, diluted with 60 ml of water and brought to pH 8 by adding approx. 8 ml concentrated hydrochloric acid. The unreacted portions of the 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethanol are then carefully extracted with diethyl ether, enabling the recovery of 7.3 g after evaporation of the solvent.
Den vandige fase, som inneholder natriumsaltet av den ønskede syre, surgjøres til pH 5 ved tilsetning av saltsyre og ekstraheres tre ganger med 200 ml diklormethan. De organiske faser som fåes ved ekstraksjonen, slåes sammen og tørres over magnesiumsulfat, filtreres, og inndampes i en roterende inndamper. Det fåes en olje som tillates å krystallisere mens den fortsatt er varm, ved tilsetning av 150 ml 2-butanon. Det faste stoff som dannes, frafiltreres og tørres. Det oppnås derved 32,7 g 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazin-yl] -ethoxy]-syre. The aqueous phase, which contains the sodium salt of the desired acid, is acidified to pH 5 by the addition of hydrochloric acid and extracted three times with 200 ml of dichloromethane. The organic phases obtained during the extraction are combined and dried over magnesium sulphate, filtered and evaporated in a rotary evaporator. An oil is obtained which is allowed to crystallize while it is still hot, by adding 150 ml of 2-butanone. The solid that forms is filtered off and dried. 32.7 g of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazin-yl]-ethoxy]-acid are thereby obtained.
Utbytte: 55,5%. Smeltepunkt 146-148°C. Yield: 55.5%. Melting point 146-148°C.
Analyse for C21<H>25C1N203i % Analysis for C21<H>25C1N203i %
En andre porsjon produkt kan fåes ved konsentrering av moder-luten (7,4 g). 3. 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid. A second portion of product can be obtained by concentrating the mother liquor (7.4 g). 3. 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride.
32,7 g 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-pipera-zinyl] -ethoxy]-eddiksyre oppslemmes i en blanding av 125 ml vann og 13,8 ml 37%-ig vandig saltsyre. Denne blanding kon-sentreres i en roterende inndamper. Det fåes en olje som krystalliseres ved tilsetning av 245 ml 2-butanon. De dannede krystaller frafiltreres, avsuges og tørres. Det fåes 34,2 g 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid. 32.7 g of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid are suspended in a mixture of 125 ml of water and 13.8 ml of 37% aqueous hydrochloric acid. This mixture is concentrated in a rotary evaporator. An oil is obtained which crystallizes by adding 245 ml of 2-butanone. The formed crystals are filtered off, suctioned off and dried. 34.2 g of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride are obtained.
Utbytte: 88%. Smeltepunkt: 228,22°C. (Differensiell avsøkende kalorimetri, DSC). Yield: 88%. Melting point: 228.22°C. (Differential scanning calorimetry, DSC).
Analyse for C21H25C1N203- 2HC1 i % Analysis for C21H25C1N203- 2HC1 in %
beregnet: C 54,56 H 5,84 N 6,06 Cl" 15,37 Cl<tot->23,05 funnet: C 54,28 H 5,86 N 6,15 Cl" 15,24 Cl<tot->23,22. calculated: C 54.56 H 5.84 N 6.06 Cl" 15.37 Cl<tot->23.05 found: C 54.28 H 5.86 N 6.15 Cl" 15.24 Cl<tot- >23.22.
En andre porsjon dihydroklorid kan fåes på den samme måte ved at man starter med den andre porsjon produkt oppnådd under A second portion of dihydrochloride can be obtained in the same way by starting with the second portion of product obtained below
punkt 2 ovenfor (4,5 g). point 2 above (4.5 g).
Tatt i betraktning at 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethanolen fåes i et utbytte på 90,4% fra l-[(4-klorfenyl)-fenylmethyl]-piperazin, fåes således 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid i tre trinn i et totalt utbytte på 44,1% (idet et utbytte på mer enn 48% er mulig ved resirkulering av uom-satt 2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethanol), hvilket representerer en markert forbedring i forhold til fremgangsmåten ifølge europeisk patentskrift nr. 58 146. Considering that the 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethanol is obtained in a yield of 90.4% from 1-[(4-chlorophenyl)-phenylmethyl]-piperazine, we obtain thus 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride in three steps in a total yield of 44.1% (where a yield of more than 48 % is possible by recycling unreacted 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethanol), which represents a marked improvement compared to the method according to European Patent Document No. 58 146.
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888827390A GB8827390D0 (en) | 1988-11-23 | 1988-11-23 | Process for preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-pipera-zinyl)ethoxy)-acetic acid & its dihydrochloride |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO894650D0 NO894650D0 (en) | 1989-11-22 |
| NO894650L NO894650L (en) | 1990-05-25 |
| NO172287B true NO172287B (en) | 1993-03-22 |
| NO172287C NO172287C (en) | 1993-06-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| NO894650A NO172287C (en) | 1988-11-23 | 1989-11-22 | PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -ACETIC ACID AND ITS DIHYDROCHLORIDE |
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| KR (1) | KR970009727B1 (en) |
| AT (1) | AT398970B (en) |
| CA (1) | CA1320732C (en) |
| CY (1) | CY1696A (en) |
| DK (1) | DK174289B1 (en) |
| ES (1) | ES2018967A6 (en) |
| FI (1) | FI91861C (en) |
| GB (2) | GB8827390D0 (en) |
| GR (1) | GR1000576B (en) |
| HK (1) | HK45493A (en) |
| HU (1) | HU208002B (en) |
| NO (1) | NO172287C (en) |
| PH (1) | PH26334A (en) |
| PL (1) | PL161374B1 (en) |
| PT (1) | PT92363B (en) |
| RU (1) | RU1838306C (en) |
| SG (1) | SG12793G (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2145413A1 (en) * | 1992-09-24 | 1994-03-31 | Nancy M. Gray | Methods and compositions for treating allergic disorders using optically pure (+) cetirizine |
| DK0663828T3 (en) * | 1992-09-24 | 1999-06-07 | Sepracor Inc | Treatment of allergic rhinitis and asthma using (-) cetirizine |
| BE1010094A3 (en) * | 1996-04-10 | 1997-12-02 | Ucb Sa | NEW [2- (1-piperazinyl) ethoxy] SUBSTITUTED. |
| BE1010095A3 (en) * | 1996-04-10 | 1997-12-02 | Ucb Sa | METHOD OF PREPARATION OF ACID 2- [2- [4 - [(4-Chlorophenyl) phenylmethyl] -1-PIPERAZINYL] ETHOXY] acetic acid AND ITS SALTS. |
| CA2180993A1 (en) * | 1996-07-11 | 1998-01-12 | Yong Tao | Methods for the manufacture of cetirizine |
| EP0919550A1 (en) * | 1997-11-26 | 1999-06-02 | Ucb, S.A. | Pseudopolymorphic forms of 2-2-4-bis(4-fluorophenyl)methyl-1-piperazinyl-ethoxy acetic acid dihydrochloride |
| IL124195A (en) * | 1998-04-23 | 2000-08-31 | Chemagis Ltd | Process for the preparation of esters of 2-¬4-¬4-chlorophenyl¾phenylmethyl¾-1-piperazinyl¬ethoxy¾acetic acid |
| DK176706B1 (en) * | 1999-03-04 | 2009-03-30 | Sandoz As | Process for the preparation of 2- {2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy} -acetic acid compounds or salts thereof |
| US6265579B1 (en) * | 1999-10-29 | 2001-07-24 | Salsbury Chemicals, Inc. | Process for preparing piperazine-substituted aliphatic carboxylates |
| US7199241B1 (en) | 2001-05-29 | 2007-04-03 | Ucb, S.A. | Process for preparing (S) and (R)-2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide |
| US6977301B1 (en) | 2001-05-29 | 2005-12-20 | Ucb, S.A. | Process for preparing (S) and (R)—2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide |
| AU2003238883A1 (en) * | 2002-06-05 | 2003-12-22 | Dr.Reddy's Laboratories Ltd. | A novel amorphous form of (2-(4-((4-chlorophenyl)-phenyl methyl)-1- piperazinyl) ethoxy) acetic acid dihydrochloride (cetirizine dihydrochloride) |
| EP1590323A2 (en) | 2003-01-23 | 2005-11-02 | Ucb Farchim, S.A. | Piperazine derivatives and their use as synthesis intermediates |
| AU2003228011A1 (en) * | 2003-05-21 | 2004-12-13 | Wockhardt Limited | 2-(2-(4-((4-chlorophenyl) phenylmethyl)-1-piperazinyl)ethoxy)acetic acid monohydrochloride as anti-allergenic compound and process for its production |
| US20110172425A1 (en) | 2008-09-17 | 2011-07-14 | Calyx Chemicals And Pharmaceuticals Pvt. Ltd. | Novel water based process for the preparation of substituted diphenylmethyl piperazines |
| KR101418404B1 (en) | 2012-01-06 | 2014-07-10 | 한미약품 주식회사 | Stable pharmaceutical formulation for oral administration comprising levocetirizine or a pharmaceutically acceptable salt thereof, and montelukast or a pharmaceutically acceptable salt thereof |
| KR102226833B1 (en) | 2013-06-28 | 2021-03-12 | 한미약품 주식회사 | Complex granule formulation having improved stability comprising levocetirizine and montelukast |
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| GB817231A (en) * | 1956-01-27 | 1959-07-29 | Henri Morren | New derivatives of n-mono-benzhydryl-piperazine and process for the preparation thereof |
| US3090725A (en) * | 1960-02-29 | 1963-05-21 | Burroughs Wellcome Co | Phosphorylated quaternary ammonium compounds of improved oral absorption |
| FI75816C (en) * | 1981-02-06 | 1988-08-08 | Ucb Sa | Process for the preparation of therapeutically active 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid or its amide |
-
1988
- 1988-11-23 GB GB888827390A patent/GB8827390D0/en active Pending
-
1989
- 1989-09-29 CA CA000614708A patent/CA1320732C/en not_active Expired - Fee Related
- 1989-11-20 GR GR890100771A patent/GR1000576B/en not_active IP Right Cessation
- 1989-11-21 GB GB8926242A patent/GB2225320B/en not_active Expired - Lifetime
- 1989-11-21 PT PT92363A patent/PT92363B/en not_active IP Right Cessation
- 1989-11-22 FI FI895563A patent/FI91861C/en not_active IP Right Cessation
- 1989-11-22 AT AT0266489A patent/AT398970B/en not_active IP Right Cessation
- 1989-11-22 NO NO894650A patent/NO172287C/en not_active IP Right Cessation
- 1989-11-22 RU SU894742406A patent/RU1838306C/en active
- 1989-11-22 PL PL1989282411A patent/PL161374B1/en unknown
- 1989-11-22 ES ES8903974A patent/ES2018967A6/en not_active Expired - Lifetime
- 1989-11-22 DK DK198905865A patent/DK174289B1/en not_active IP Right Cessation
- 1989-11-22 HU HU896130A patent/HU208002B/en not_active IP Right Cessation
- 1989-11-23 KR KR1019890017039A patent/KR970009727B1/en not_active IP Right Cessation
- 1989-11-23 PH PH39569A patent/PH26334A/en unknown
-
1993
- 1993-02-06 SG SG127/93A patent/SG12793G/en unknown
- 1993-05-13 HK HK454/93A patent/HK45493A/en not_active IP Right Cessation
-
1994
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Also Published As
| Publication number | Publication date |
|---|---|
| FI91861C (en) | 1994-08-25 |
| FI91861B (en) | 1994-05-13 |
| NO894650L (en) | 1990-05-25 |
| GB2225320A (en) | 1990-05-30 |
| PT92363A (en) | 1990-05-31 |
| GB2225320B (en) | 1992-09-02 |
| FI895563A0 (en) | 1989-11-22 |
| DK586589D0 (en) | 1989-11-22 |
| DK174289B1 (en) | 2002-11-18 |
| GB8926242D0 (en) | 1990-01-10 |
| HU896130D0 (en) | 1990-02-28 |
| GR1000576B (en) | 1992-08-26 |
| KR970009727B1 (en) | 1997-06-17 |
| HUT53626A (en) | 1990-11-28 |
| HU208002B (en) | 1993-07-28 |
| CA1320732C (en) | 1993-07-27 |
| KR900007824A (en) | 1990-06-02 |
| ES2018967A6 (en) | 1991-05-16 |
| PL161374B1 (en) | 1993-06-30 |
| SG12793G (en) | 1993-04-16 |
| ATA266489A (en) | 1994-07-15 |
| PH26334A (en) | 1992-04-29 |
| HK45493A (en) | 1993-05-21 |
| RU1838306C (en) | 1993-08-30 |
| DK586589A (en) | 1990-05-24 |
| GB8827390D0 (en) | 1988-12-29 |
| NO172287C (en) | 1993-06-30 |
| AT398970B (en) | 1995-02-27 |
| NO894650D0 (en) | 1989-11-22 |
| PT92363B (en) | 1995-07-18 |
| CY1696A (en) | 1994-01-14 |
| GR890100771A (en) | 1990-12-31 |
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