NO172342B - PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -DETIC ACID AND ITS DIHYDROCHLORIDE, AND INTERMEDIATE PRODUCT FOR USE BY FRAME - Google Patents
PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -DETIC ACID AND ITS DIHYDROCHLORIDE, AND INTERMEDIATE PRODUCT FOR USE BY FRAME Download PDFInfo
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- NO172342B NO172342B NO894651A NO894651A NO172342B NO 172342 B NO172342 B NO 172342B NO 894651 A NO894651 A NO 894651A NO 894651 A NO894651 A NO 894651A NO 172342 B NO172342 B NO 172342B
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- Prior art keywords
- phenylmethyl
- chlorophenyl
- ethoxy
- piperazinyl
- dihydrochloride
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- 239000002253 acid Substances 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 5
- -1 2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY Chemical class 0.000 title description 3
- 239000013067 intermediate product Substances 0.000 title description 2
- 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 claims abstract description 14
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 14
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 18
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- SBAKHIDRFYZRKO-UHFFFAOYSA-N 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetonitrile Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCN(CCOCC#N)CC1 SBAKHIDRFYZRKO-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 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 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 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 10
- 238000003756 stirring Methods 0.000 description 9
- 239000002609 medium Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229960001803 cetirizine Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- GQFCLJZQECVTDO-UHFFFAOYSA-N 2-(2-chloroethoxy)acetonitrile Chemical compound ClCCOCC#N GQFCLJZQECVTDO-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 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 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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 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
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 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
- 239000002547 new drug 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
- 239000000843 powder Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 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)
Abstract
Ny fremgangsmåte for fremstilling av 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre og dens dihydroklorid, hvor 2-[2-[4-[(4-klorfenyl)-fenyImethyl]-1-piperazinyl]-ethoxy]-acetonitril hydrolyseres i et vandig, alkoholisk eller vandig-alkoholisk medium med en base eller med en syre, og den derved oppnådde syre om ønskes overfares til dens dihydroklorid.New process for the preparation of 2- [2- [4 - [(4-chlorophenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid and its dihydrochloride, wherein 2- [2- [4 - [(4-chlorophenyl) ) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetonitrile is hydrolyzed in an aqueous, alcoholic or aqueous-alcoholic medium with a base or with an acid, and the acid thus obtained, if desired, is transferred to its dihydrochloride.
Description
Den foreliggende oppfinnelse angår en ny fremgangsmåte for fremstilling av 2-[2-[4-[(4-klorfenyl)-fenylmethy1]-1-piperazinyl]-ethoxy]-eddiksyre med formelen: The present invention relates to a new process for the production of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid with the formula:
i den venstredreiende form, i den høyredreiende form eller i form av en blanding av den venstredreiende og den høyre-dreiende form, og dens dihydroklorid. I formelen indikerer stjernen molekylets asymmetrisentrum. in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the levorotatory and dextrorotatory forms, and its dihydrochloride. In the formula, the star indicates the molecule's center of asymmetry.
Oppfinnelsen angår også et mellomprodukt som benyttes ved fremgangsmåten. The invention also relates to an intermediate product used in the method.
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. 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.
I europeisk patentskrift nr. 58 146 beskrives en syntese for fremstilling av 2-[2-[4-[(4-klorfenyl)-fenyl-methyl]-1-piperazinyl]-ethoxy]-eddiksyre og dens dihydroklorid. I denne syntese er utgangsmaterialet 1-[(4-klorfenyl)-fenylmethyl]-piperazin, og dette omsettes med methyl-(2-klor-ethoxy)-acetat, hvorved det fåes methyl-2-[2-[4-[(4-klor-fenyl ) -f enylmethyl] -1-piperazinyl] -ethoxy- acetat i et utbytte på 27,8%. Denne methylester underkastes så hydrolyse med en uorganisk base (kalium- eller natriumhydroxyd), hvorved nat-rium- 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)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid and its dihydrochloride. In this synthesis, the starting material is 1-[(4-chlorophenyl)-phenylmethyl]-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.
Med den foreliggende oppfinnelse tilveiebringes det nu en ny fremgangsmåte som muliggjør fremstilling av 2-[2-[4-[ ( 4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre i de ovenfor angitte former, og forbindelsens dihydroklorid, i bedre utbytte. With the present invention, a new method is now provided which enables the production of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid in the forms stated above, and the compound's dihydrochloride , in better dividends.
Den nye fremgangsmåte er karakteristisk ved at l-[(4-klorfenyl)-fenylmethyl]-1-piperazin med formelen: The new method is characteristic in that l-[(4-chlorophenyl)-phenylmethyl]-1-piperazine with the formula:
i den venstredreiende form, i den høyredreiende form eller i form av en blanding av den venstredreiende og den høyre-dreiende form, omsettes, i nærvær av en syreakseptor, med et 2-halogenethoxyacetonitril med formelen: hvor X er et halogenatom, og det resulterende 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-acetonitril med formelen: in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the levorotatory and dextrorotatory forms, is reacted, in the presence of an acid acceptor, with a 2-haloethoxyacetonitrile of the formula: where X is a halogen atom, and the resulting 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile with the formula:
i den venstredreiende form, i den høyredreiende form eller i form av en blanding av den høyredreiende og venstredreiende form, hydrolyseres i et vandig, alkoholisk eller vandig-al- in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the dextrorotatory and levorotatory forms, is hydrolyzed in an aqueous, alcoholic or aqueous-al-
koholisk medium med en base eller med en syre, og at den derved oppnådde syre med formel I, om nødvendig, overføres til dens dihydroklorid. alcoholic medium with a base or with an acid, and that the thereby obtained acid of formula I is, if necessary, transferred to its dihydrochloride.
Oppfinnelsen angår også 2-[2-[4-[(4-klorfenyl)-fenyl-methyl]-1-piperazinyl)-ethoxy]-acetonitrilet med formel II, som fås som et mellomprodukt ved den nye fremgangsmåte, i den venstredreiende form, i den høyredreiende form eller i form av en blanding av den venstredreiende og den høyredreiende form. The invention also relates to the 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl)-ethoxy]-acetonitrile of formula II, which is obtained as an intermediate by the new process, in the left-handed form , in the right-handed form or in the form of a mixture of the left-handed and right-handed forms.
Forbindelsen med formel II fås i henhold til ligningen: The compound of formula II is obtained according to the equation:
hvor X betegner et halogenatom. where X denotes a halogen atom.
Denne reaksjon utføres i nærvær av en syreakseptor, som f.eks. et alkalimetallcarbonat, og eventuelt i nærvær av en liten mengde av et alkalimetalljodid for å akselerere reaksjonen, i et inert organisk oppløsningsmiddel, som f.eks. en alkohol (f.eks. n-butanol, osv.), fortrinnsvis ved en temperatur nær tilbakeløpstemperaturen. This reaction is carried out in the presence of an acid acceptor, such as e.g. an alkali metal carbonate, and optionally in the presence of a small amount of an alkali metal iodide to accelerate the reaction, in an inert organic solvent, such as an alcohol (eg n-butanol, etc.), preferably at a temperature close to the reflux temperature.
Når et optisk aktivt 1-[(4-klorfenyl)-fenylmethyl]-piperazin med formel III benyttes i denne reaksjon istedenfor racematet, kan den som utgangsmateriale benyttede enantiomer fås ved optisk spaltning av den tilsvarende racemiske forbin- When an optically active 1-[(4-chlorophenyl)-phenylmethyl]-piperazine of formula III is used in this reaction instead of the racemate, the enantiomer used as starting material can be obtained by optical cleavage of the corresponding racemic compound
deise etter i og for seg kjente metoder. these according to methods known in and of themselves.
Blant de optisk aktive syrer som kan benyttes ved denne optiske spaltning, foretrekkes vinsyre. Among the optically active acids that can be used in this optical cleavage, tartaric acid is preferred.
Hva angår 2-halogenethoxyacetonitrilene med formelen IV, og spesielt 2-klorethoxyacetonitril, kan disse forbin-delser fremstilles i henhold til metoden beskrevet av E.J. Salmi et al., Suomen Kemistilehti, 17B, (1944), 17-19 (Chem.Abstr. 40, (1946), 6491). As regards the 2-haloethoxyacetonitrile of the formula IV, and especially 2-chloroethoxyacetonitrile, these compounds can be prepared according to the method described by E.J. Salmi et al., Suomen Kemistilehti, 17B, (1944), 17-19 (Chem.Abstr. 40, (1946), 6491).
2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyren med formel I fåes ved hydrolyse av 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-acetonit-rilet med formelen II i henhold til ligningen: The 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid of formula I is obtained by hydrolysis of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl] ]-1-piperazinyl]-ethoxy]-acetonitrile of the formula II according to the equation:
Denne hydrolyse kan utføres på to måter, nemlig i et basisk medium og i et surt medium. 1. Hydrolyse av nitrilet i et basisk medium Nitrilet med formelen II oppvarmes i nærvær av en uorganisk base, som f.eks. et alkalimetallhydroxyd, i et vandig, alkoholisk eller vandig-alkoholisk medium (methanol, ethanol, osv.), ved en temperatur mellom 60°C og reaksjonsblandingens tilbakeløpstemperatur. This hydrolysis can be carried out in two ways, namely in a basic medium and in an acidic medium. 1. Hydrolysis of the nitrile in a basic medium The nitrile with the formula II is heated in the presence of an inorganic base, such as e.g. an alkali metal hydroxide, in an aqueous, alcoholic or aqueous-alcoholic medium (methanol, ethanol, etc.), at a temperature between 60°C and the reflux temperature of the reaction mixture.
Den dannede syre med formel I er tilstede i reaksjonsblandingen i form av dens alkalimetallsalt, fra hvilket syren frigjøres ved surgjøring av reaksjonsblandingen med en uorganisk syre (f.eks. saltsyre ). Syren med formel I ekstraheres deretter med et organisk oppløsningsmiddel (diklormethan, toluen, osv.) og isoleres ved krystallisasjon. Til slutt overføres syren med formel I til dihydrokloridet på i og for seg kjent måte. The formed acid of formula I is present in the reaction mixture in the form of its alkali metal salt, from which the acid is liberated by acidifying the reaction mixture with an inorganic acid (e.g. hydrochloric acid). The acid of formula I is then extracted with an organic solvent (dichloromethane, toluene, etc.) and isolated by crystallization. Finally, the acid of formula I is transferred to the dihydrochloride in a manner known per se.
2. Hydrolyse av nitrilet i et surt medium 2. Hydrolysis of the nitrile in an acidic medium
Nitrilet med formel II oppvarmes i nærvær av en uorganisk syre, som f.eks. saltsyre, fortrinnsvis i et vandig medium, ved en temperatur mellom 60 °C og reaksjonsblandingens tilbakeløpstemperatur. Den dannede syre med formel I ekstraheres så fra reaksjonsblandingen med et organisk oppløsningsmiddel (diklormethan, toluen, osv.) og renses ved krystallisasjon. Den frie syre med formel I overføres så til dihydrokloridet på i og for seg kjent måte. The nitrile of formula II is heated in the presence of an inorganic acid, such as hydrochloric acid, preferably in an aqueous medium, at a temperature between 60 °C and the reflux temperature of the reaction mixture. The formed acid of formula I is then extracted from the reaction mixture with an organic solvent (dichloromethane, toluene, etc.) and purified by crystallization. The free acid of formula I is then transferred to the dihydrochloride in a manner known per se.
Den nye fremgangsmåte gir cetirizin-dihydroklorid i totalutbytter, beregnet på den benyttede mengde 1-[(4-klor-fenyl )-fenylmethyl]-piperazin, på 60% eller mer ved sur hydrolyse og 65% eller mer ved basisk hydrolyse. Dessuten kan det oppnås meget høye utbytter av de optisk aktive former av denne forbindelse ved denne fremgangsmåte, f.eks. et utbytte på 57% eller mer av cetirizin-dihydroklorid i den høyredreiende form, beregnet på mengden av det benyttede 1-[(4-klorfenyl)-fenyl-metyl]-piperazin i venstredreiende form. Disse høyere utbytter, som oppnås ved at man starter med 1-[( 4-klorfenyl)-fenyl-methyl]-piperazin, representerer et betydelig teknisk frem-skritt sammenlignet med fremgangsmåten beskrevet i europeisk patentskrift nr. 58 146. The new method gives cetirizine dihydrochloride in total yields, calculated on the amount of 1-[(4-chloro-phenyl)-phenylmethyl]-piperazine used, of 60% or more by acid hydrolysis and 65% or more by basic hydrolysis. Moreover, very high yields of the optically active forms of this compound can be obtained by this method, e.g. a yield of 57% or more of cetirizine dihydrochloride in the dextrorotatory form, calculated on the amount of 1-[(4-chlorophenyl)-phenyl-methyl]-piperazine in the levorotatory form used. These higher yields, which are obtained by starting with 1-[(4-chlorophenyl)-phenyl-methyl]-piperazine, represent a significant technical advance compared to the method described in European Patent Document No. 58 146.
De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksempel Example
Fremstilling av racemisk 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid med formel I. Preparation of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I.
1. Racemisk 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazi-nyl] -ethoxy]-acetonitril med formel II 1. Racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile of formula II
200 ml n-butanol, 43,05 g (0,15 mol) racemisk l-[(4-klorfenyl)-fenylmethyl]-piperazin, 24 g (0,174 mol) 2-klorethoxyacetonitril, 26,1 g (0,246 mol) natriumcarbonat og 0,78 g (0,0047 mol) kaliumjodid innføres i tur og orden i en tre-halset rundkolbe utstyrt med en mekanisk rører, en kondensator og et termometer. Blandingen oppvarmes ved 110°C i elleve timer under omrøring, avkjøles, filtreres og inndampes i en 200 ml n-butanol, 43.05 g (0.15 mol) racemic l-[(4-chlorophenyl)-phenylmethyl]-piperazine, 24 g (0.174 mol) 2-chloroethoxyacetonitrile, 26.1 g (0.246 mol) sodium carbonate and 0.78 g (0.0047 mol) of potassium iodide are introduced in turn into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The mixture is heated at 110°C for eleven hours with stirring, cooled, filtered and evaporated in a
roterende inndamper. 60 g av en gulbrun olje isoleres og rotary evaporator. 60 g of a yellow-brown oil is isolated and
kromatograferes i en kolonne som inneholder 1 kg silica, under anvendelse av en blanding inneholdende 98 vol% diklormethan og 2 vol% methanol. Det ønskede nitril oppsamles i to fraksjoner, fra hvilke oppløsningsmidlene fjernes. Renheten av fraksjonene måles ved væskekromatografering med høy ytelse. (HP). is chromatographed in a column containing 1 kg of silica, using a mixture containing 98 vol% dichloromethane and 2 vol% methanol. The desired nitrile is collected in two fractions, from which the solvents are removed. The purity of the fractions is measured by high-performance liquid chromatography. (HP).
Racemisk 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-pipe-razinyl] -1-ethoxy] -acetonitril fåes derved i to fraksjoner, den ene på 33,6 g med en renhet på 100% og den andre på 14,4 g med en renhet på 97,4%. Racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-pipe-razinyl]-1-ethoxy]-acetonitrile is thereby obtained in two fractions, one of 33.6 g with a purity of 100 % and the other of 14.4 g with a purity of 97.4%.
Utbytte: 86,4%. Yield: 86.4%.
Den oppnådde forbindelse kan identifiseres i form av dens dihydroklorid fremstilt fra en ethanolisk oppløsning av gassformig hydrogenklorid. The compound obtained can be identified in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrogen chloride.
Smeltepunkt: 201-202°C. Melting point: 201-202°C.
Analyse for C21H24C1N30- 2HC1 i % Analysis for C21H24C1N30- 2HC1 in %
beregnet: C 56,96 H 5,91 N 9,48 Cl' 16,01 Cl<tot-> 24,02 funnet: C 57,21 H 6,00 N 9,49 Cl" 15,78 Cl<tot-> 23,76. 2. Racemisk 2- f2- T4- I" ( 4- klorfenyl)- f enylmethyl 1 - 1- piperazi-nyll- ethoxy]- eddiksyre med formel I (ved hydrolyse i et basisk medium). calculated: C 56.96 H 5.91 N 9.48 Cl' 16.01 Cl<tot-> 24.02 found: C 57.21 H 6.00 N 9.49 Cl" 15.78 Cl<tot- > 23.76. 2. Racemic 2-f2-T4-I" (4-chlorophenyl)-phenylmethyl 1-1-piperazinyl-ethoxy]-acetic acid of formula I (by hydrolysis in a basic medium).
250 g ethanol, 23 g (0,062 mol) racemisk 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-acetonitril og 31 ml av en 4N ethanolisk oppløsning av kaliumhydroxyd inn-føres i tur og orden i en tre-halset rundkolbe utstyrt med en mekanisk rører, en kondensator og et termometer. Reaksjonsblandingen kokes med tilbakeløpskjøling i 10 timer under omrøring. Reaksjonsblandingen tillates å avkjøles, og dens pH bringes til 6 ved tilsetning av 37% konsentrert saltsyre. Ethanolen avdampes, og reaksjonsblandingen fortynnes med 100 ml vann og ekstraheres tre ganger med 200 ml diklormethan. De organiske faser slåes sammen, tørres over magnesiumsulfat, filtreres og inndampes i en roterende inndamper. Det fåes en olje, som tillates å krystallisere varmt ved tilsetning av 100 ml 2-butanon. Det dannede faste stoff frafiltreres, vaskes og tørres. Det fåes derved 18,9 g racemisk 2-[2-[4-[(4-klorfe-nyl )-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre. 250 g ethanol, 23 g (0.062 mol) racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile and 31 ml of a 4N ethanolic solution of potassium hydroxide in are introduced in turn into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The reaction mixture is boiled under reflux for 10 hours with stirring. The reaction mixture is allowed to cool and its pH is brought to 6 by the addition of 37% concentrated hydrochloric acid. The ethanol is evaporated, and the reaction mixture is diluted with 100 ml of water and extracted three times with 200 ml of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated in a rotary evaporator. An oil is obtained, which is allowed to crystallize hot by the addition of 100 ml of 2-butanone. The solid formed is filtered off, washed and dried. 18.9 g of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid are thereby obtained.
18,9 g av den oppnådde syre oppslemmes på ny i 150 ml vann, og pH-verdien innstilles på 0,8 ved tilsetning av konsentrert saltsyre. Den vandige oppløsning konsentreres i en roterende inndamper, hvoretter residuet fortynnes ved tilsetning av 75 ml 2-butanon og det på ny foretas konsentrering. Ved tilsetning av 150 ml 2-butanon til det således oppnådde residuum avstedkommes krystallisasjon av racemisk 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid. Krystallene frafiltreres og tørres. Det oppnås 21,7 g av den ønskede forbindelse. 18.9 g of the acid obtained is resuspended in 150 ml of water, and the pH value is adjusted to 0.8 by adding concentrated hydrochloric acid. The aqueous solution is concentrated in a rotary evaporator, after which the residue is diluted by adding 75 ml of 2-butanone and concentration is carried out again. By adding 150 ml of 2-butanone to the thus obtained residue, crystallization of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride takes place. The crystals are filtered off and dried. 21.7 g of the desired compound are obtained.
Utbytte: 75,9%. Smeltepunkt: 220,15°C. (Differensiell av-søkende kalorimetri; DSC) (spaltes ved smeltning). Yield: 75.9%. Melting point: 220.15°C. (Differential Scanning Calorimetry; DSC) (decomposes on melting).
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 54,60 H 5,86 N 6,02 Cl' 15,33 Cl<tot-> 23,26 calculated: C 54.56 H 5.84 N 6.06 Cl" 15.37 Cl<tot-> 23.05 found: C 54.60 H 5.86 N 6.02 Cl' 15.33 Cl<tot- > 23.26
Det totale utbytte av dikloridet av 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre, beregnet på den benyttede mengde 1-[(4-klorfenyl)-fenylmethyl]-piperazin, er 65,6%. 3. Racemisk 2-f2-f4-f( 4- klorfenyl)- fenylmethyl]- 1- piperazin-yl 1- ethoxy]- eddiksyre med formel I (ved hydrolyse i et surt medium). 45,3 g (0,123 mol) racemisk 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-acetonitril innføres i en reaktor utstyrt med en mekanisk rører, en kondensator, et termometer og en dråpetrakt og oppvarmes til 45°C under omrøring. 41 ml 37% konsentrert saltsyre tilsettes så dråpevis. Reaksjonsblandingens temperatur øker til 92°C. Reaksjonsblandingen oppvarmes ved 95°C i 90 minutter under omrøring. Reaksjonsblandingen tillates å avkjøles inndampes i en roterende inndamper. Residuet taes opp i 150 ml toluen, og reaksjonsblandingen inndampes på ny i en roterende inndamper. Residuet oppløses i 200 ml vann, og den oppnådde vandige oppløsning innstilles på pH 5 ved tilsetning av natriumhydroxyd. Opp-løsningen ekstraheres tre ganger med 300 ml diklormethan. De organiske faser slås sammen, og oppløsningsmidlet fjernes i en roterende inndamper. Den derved oppnådde olje tillates å krystallisere varmt ved at den dispergeres i 250 ml 2-butanon. The total yield of the dichloride of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid, calculated on the amount of 1-[(4-chlorophenyl)-phenylmethyl] used -piperazine, is 65.6%. 3. Racemic 2-f2-f4-f(4-chlorophenyl)-phenylmethyl]-1-piperazin-yl 1-ethoxy]-acetic acid of formula I (by hydrolysis in an acidic medium). 45.3 g (0.123 mol) of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile is introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and heated to 45°C while stirring. 41 ml of 37% concentrated hydrochloric acid is then added drop by drop. The temperature of the reaction mixture increases to 92°C. The reaction mixture is heated at 95°C for 90 minutes with stirring. The reaction mixture is allowed to cool and evaporated in a rotary evaporator. The residue is taken up in 150 ml of toluene, and the reaction mixture is re-evaporated in a rotary evaporator. The residue is dissolved in 200 ml of water, and the resulting aqueous solution is adjusted to pH 5 by adding sodium hydroxide. The solution is extracted three times with 300 ml of dichloromethane. The organic phases are combined, and the solvent is removed in a rotary evaporator. The oil thus obtained is allowed to crystallize hot by dispersing it in 250 ml of 2-butanone.
Blandingen kjøles og filtreres, og krystallene tør-res. Det oppnås derved 34 g racemisk 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre. 34 g av den derved oppnådde syre oppslemmes på ny i 300 ml vann, og pH-verdien innstilles på 0,8 ved tilsetning av konsentrert saltsyre. Den vandige oppløsning inndampes i en roterende inndamper, og residuet fortynnes ved tilsetning av 150 ml 2-butanon, hvoretter blandingen på ny inndampes. Ved tilsetning av 300 ml 2-butanon til den således oppnådde rest avstedkommes krystallisasjon av racemisk 2-[2-[4-[(4-klor-fenyl )-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid. Krystallene frafiltreres og tørres, hvorved det oppnås 39,7 g av den ønskede forbindelse. The mixture is cooled and filtered, and the crystals are dried. 34 g of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid are thereby obtained. 34 g of the acid thus obtained is resuspended in 300 ml of water, and the pH value is adjusted to 0.8 by adding concentrated hydrochloric acid. The aqueous solution is evaporated in a rotary evaporator, and the residue is diluted by adding 150 ml of 2-butanone, after which the mixture is evaporated again. By adding 300 ml of 2-butanone to the residue thus obtained, crystallization of racemic 2-[2-[4-[(4-chloro-phenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride is effected. The crystals are filtered off and dried, whereby 39.7 g of the desired compound are obtained.
Utbytte: 70%. Smeltepunkt: 227,02°C. (DSC) (spaltes ved smeltning). Yield: 70%. Melting point: 227.02°C. (DSC) (decomposes on melting).
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 54,30 H 5,88 N 6,83 Cl" 15,56 Cl<tot-> 23,06 calculated: C 54.56 H 5.84 N 6.06 Cl" 15.37 Cl<tot-> 23.05 found: C 54.30 H 5.88 N 6.83 Cl" 15.56 Cl<tot- > 23.06
Det totale utbytte av 2-[2-[4-[(4-klorfenyl)-fenyl-methyl] -1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid, beregnet på den benyttede mengde 1-[(4-klorfenyl)-fenylmethyl]-piperazin, er 60,5%. The total yield of 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride, calculated on the amount of 1-[(4-chlorophenyl)- phenylmethyl]-piperazine, is 60.5%.
Eksempel 2 Example 2
Fremstilling av høyredreiende 2-[2-[4-[(4-klorfenyl)-fenyl-methyl] -1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid med formel I Preparation of dextrorotatory 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I
1. Venstredreiende 1-[(4-klorfenyl)-fenylmethyl]-piperazin med formel III 1. Levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine of formula III
En oppløsning av 300 g (2 mol) (2R,3R)-vinsyre i 2 1 ethanol oppvarmes ved 72-74°C, og en oppløsning av 286,5 g (1 mol) racemisk 1-[(4-klorfenyl)-fenylmethyl]-piperazin ill ethanol tilsettes under omrøring. Blandingen kokes med til-bakeløpskjøling i 5 minutter og tillates deretter å avkjøles til romtemperatur under omrøring (det ønskede salt begynner å krystallisere når temperaturen nærmer seg 57°C). Det oppnådde salt frafiltreres og omkrystalliseres tre ganger etter hver-andre, først i en blanding av 2 1 ethanol og 0,8 1 methanol, deretter ill ethanol og til slutt i en blanding av 0,5 1 ethanol, 65 ml methanol og 5 ml vann. Etter frafiltrering og tørring fåes 118 g diastereoisomert urent 1-[4-klorfenyl)-fenylmethyl]-piperazin (2R,3%)-tartrat. Smeltepunkt 170, 4°C A solution of 300 g (2 mol) (2R,3R)-tartaric acid in 2 1 ethanol is heated at 72-74°C, and a solution of 286.5 g (1 mol) racemic 1-[(4-chlorophenyl)- phenylmethyl]-piperazine and ethanol are added with stirring. The mixture is refluxed for 5 minutes and then allowed to cool to room temperature with stirring (the desired salt begins to crystallize as the temperature approaches 57°C). The salt obtained is filtered off and recrystallized three times one after the other, first in a mixture of 2 1 ethanol and 0.8 1 methanol, then in ethanol and finally in a mixture of 0.5 1 ethanol, 65 ml methanol and 5 ml water. After filtering off and drying, 118 g of diastereoisomeric impure 1-[4-chlorophenyl)-phenylmethyl]-piperazine (2R,3%)-tartrate are obtained. Melting point 170, 4°C
(DSC). (DSC).
[a]^<5> : + 7,8° (c = 1, methanol). [a]^<5> : + 7.8° (c = 1, methanol).
Dette salt blir så spaltet ved tilsetning av en oppløsning av 22 g (0,55 mol) natriumhydroxyd i 750 ml vann. Derved frigjort venstredreiende 1-[(4-klorfenyl)-fenylmethyl]-piperazin ekstraheres flere ganger med diklormethan. De sam-menslåtte organiske faser tørres over natriumsulfat, filtreres og inndampes i en roterende inndamper. Det oppnås 80 g optisk urent, venstredreiende l-[(4-klorfenyl)-fenylmethyl]-pipera-zin. Denne forbindelse renses ved suksessive omkrystal-liseringer fra hexan, hvorved det til slutt fåes 18,2 g venstredreiende l-[(4-klorfenyl)-fenylmethyl]-piperazin. Smeltepunkt: 90-92°C. Smeltepunkt: 90,35°C (DSC); This salt is then cleaved by adding a solution of 22 g (0.55 mol) of sodium hydroxide in 750 ml of water. The left-handed 1-[(4-chlorophenyl)-phenylmethyl]-piperazine thereby released is extracted several times with dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and evaporated in a rotary evaporator. 80 g of optically impure, levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine are obtained. This compound is purified by successive recrystallizations from hexane, whereby 18.2 g of levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine are finally obtained. Melting point: 90-92°C. Melting point: 90.35°C (DSC);
[a]^<5> : 19,4° (c = 1, toluen). [a]^<5> : 19.4° (c = 1, toluene).
Utbytte: 12,7%. Dividend: 12.7%.
2. Venstredreiende 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-pipe-razinyl] -ethoxy]-acetonitril med formel II 2. Levorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-pipe-razinyl]-ethoxy]-acetonitrile of formula II
100 ml n-butanol, 20 g (0,07 mol) venstredreiende 1-[(4-klorfenyl)-fenylmethyl]-piperazin, 11,2 g (0,0937 mol) 2-klorethoxyacetonitril, 12,18 g (0,115 mol) natriumcarbonat og 0,36 g (0,002 mol) kaliumjodid innføres i tur og orden i en tre-halset rundkolbe utstyrt med en mekanisk rører, en kondensator og et termometer. Blandingen oppvarmes ved 110°C i syv timer under omrøring, hvoretter den avkjøles, filtreres og inndampes i en roterende inndamper. 26 g av en gulbrun olje isoleres og kromatograferes over en kolonne inneholdende 1 kg silica ved bruk av en blanding inneholdende 98 vol% diklormethan og 2 vol% methanol. 17,8% venstredreiende 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-acetonitril fåes i form av en olje. 100 ml n-butanol, 20 g (0.07 mol) levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine, 11.2 g (0.0937 mol) 2-chloroethoxyacetonitrile, 12.18 g (0.115 mol ) of sodium carbonate and 0.36 g (0.002 mol) of potassium iodide are introduced in turn into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The mixture is heated at 110°C for seven hours with stirring, after which it is cooled, filtered and evaporated in a rotary evaporator. 26 g of a yellow-brown oil is isolated and chromatographed over a column containing 1 kg of silica using a mixture containing 98 vol% dichloromethane and 2 vol% methanol. 17.8% levorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile is obtained in the form of an oil.
[ajggg: +31,8° (c = 1, methanol). Utbytte: 69%. [αjgg: +31.8° (c = 1, methanol). Yield: 69%.
Forbindelsen kan identifiseres i form av dens dihydroklorid fremstilt av en ethanolisk oppløsning av gassformig hydrogenklorid. Smeltepunkt 211-212°C. The compound can be identified in the form of its dihydrochloride prepared from an ethanolic solution of hydrogen chloride gas. Melting point 211-212°C.
[a]365: +7'18° (° = 1'methanol). [α]365: +7'18° (° = 1'methanol).
Analyse for C21<H>24C1N30- 2HC1 i % Analysis for C21<H>24C1N30- 2HC1 in %
beregnet: C 56,96 H 5,91 N 9,49 Cl" 16,01 Cl<tot-> 24,02 funnet: C 56,92 H 5,93 N 9,33 Cl" 15,76 Cl<tot-> 23,65 calculated: C 56.96 H 5.91 N 9.49 Cl" 16.01 Cl<tot-> 24.02 found: C 56.92 H 5.93 N 9.33 Cl" 15.76 Cl<tot- > 23.65
3. Høyredreiende 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-l-pipera-zinyl]-ethoxy]-eddiksyre-dihydroklorid med formel I 3. dextrorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I
9,42 g (0,0255 mol) mol) venstredreiende 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-acetonitril innføres en reaktor utstyrt med en mekanisk rører, en kondensator, et termometer og en dråpetrakt og oppvarmes til 45°C under omrøring. Det tilsettes så 15 ml 37% konsentrert saltsyre. Reaksjonsblandingens temperatur øker til 92°C. Reaksjonsblandingen oppvarmes ved 60°C i 60 minutter under om-røring. Reaksjonsblandingen tillates å avkjøles og inndampes i en roterende inndamper, og residuet taes opp i 50 ml vann. Reaksjonsblandingens pH innstilles på 5 ved tilsetning av natriumhydroxyd, og blandingen ekstraheres med flere suksessive fraksjoner av diklormethan. De organiske faser slåes sammen og tørres over magnesiumsulfat, og oppløsningsmidlet fjernes i en roterende inndamper. Det fåes derved 9,6 g av den frie syre med formel I i form av et beigefarvet pulver. Syren overføres til dihydrokloridet ved hjelp av en oppløsning av hydrogenklorid i aceton, og dihydrokloridet utkrystalliseres. Etter frafiltrering og tørring fåes 9,8 g høyredreiende 2-[2-[4-[(4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddik-syre-dihydroklorid. Renheten av denne forbindelse, målt ved væskekromatografering med høy ytelse med en chiral-stasjonær fase av o^-AGP (fra LKB Company) er på 95% med hensyn til den høyredreiende enantiomer. 9.42 g (0.0255 mol) mol) of levorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile is introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and heated to 45°C with stirring. 15 ml of 37% concentrated hydrochloric acid is then added. The temperature of the reaction mixture increases to 92°C. The reaction mixture is heated at 60°C for 60 minutes with stirring. The reaction mixture is allowed to cool and evaporate in a rotary evaporator, and the residue is taken up in 50 ml of water. The pH of the reaction mixture is adjusted to 5 by adding sodium hydroxide, and the mixture is extracted with several successive fractions of dichloromethane. The organic phases are combined and dried over magnesium sulfate, and the solvent is removed in a rotary evaporator. 9.6 g of the free acid of formula I is thereby obtained in the form of a beige-coloured powder. The acid is transferred to the dihydrochloride using a solution of hydrogen chloride in acetone, and the dihydrochloride is crystallized. After filtering off and drying, 9.8 g of dextrorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride are obtained. The purity of this compound, as measured by high performance liquid chromatography with a chiral stationary phase of o 2 -AGP (from LKB Company) is 95% with respect to the dextrorotatory enantiomer.
Smeltepunkt 199-201°C. Smeltepunkt 224,4°C (DSC). Melting point 199-201°C. Melting point 224.4°C (DSC).
[a]365: +9'4° (°= 1' vann). [a]365: +9'4° (°= 1' water).
Utbytte 83% Yield 83%
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 54,00 H 5,88 N 5,91 Cl" 15,55 Cl<tot-> 23,13 calculated: C 54.56 H 5.84 N 6.06 Cl" 15.37 Cl<tot-> 23.05 found: C 54.00 H 5.88 N 5.91 Cl" 15.55 Cl<tot- > 23.13
Det totale utbytte av høyredreiende 2-[2-[4-[( 4-klorfenyl)-fenylmethyl]-1-piperazinyl]-ethoxy]-eddiksyre-dihydroklorid, beregnet på den benyttede mengde venstredreiende 1-[(4-klor-fenyl ) -f enylmethyl] -piperazin, er 57,3%. The total yield of dextrorotatory 2-[2-[4-[( 4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride, calculated on the amount of levorotatory 1-[(4-chloro-phenyl )-phenylmethyl]-piperazine, is 57.3%.
Eksempel 3 Example 3
Fremstilling av venstredreiende 2-[2-[4-[(4-klorfenyl)-fenyl-methyl] -1-piperazinyl] -ethoxy] -eddiksyre-dihydroklorid med formel I Preparation of levorotatory 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I
Denne forbindelse fåes etter fremgangsmåten beskrevet i Eksempel 2, idet det imidlertid startes med høyredreiende 1-[( 4-klorfenyl)-fenylmethyl]-piperazin. Sistnevnte forbindelse var fremstilt som beskrevet i Eksempel 2.1, ved behandling av racematet med (2S,3S)-vinsyre. This compound is obtained according to the method described in Example 2, although it is started with dextrorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine. The latter compound was prepared as described in Example 2.1, by treating the racemate with (2S,3S)-tartaric acid.
Det venstredreiende syredihydroklorid med formel I fåes i et utbytte og med en renhet som ligger nær opp til dem som oppnås for det høyredreiende syredihydroklorid. Renheten var således på 95%, målt ved væskekromatografering med høy ytelse, med en chiral-stasjonær fase av ^-AGP (fra LKB Company). The levorotatory acid dihydrochloride of formula I is obtained in a yield and with a purity close to that obtained for the dextrorotatory acid dihydrochloride. The purity was thus 95%, as measured by high performance liquid chromatography, with a chiral stationary phase of ^-AGP (from LKB Company).
Smeltepunkt: 198-200°C. Smeltepunkt: 220,7°C (DSC) (spaltes ved smeltning). Melting point: 198-200°C. Melting point: 220.7°C (DSC) (decomposes on melting).
Claims (3)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB888827391A GB8827391D0 (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 |
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NO894651D0 NO894651D0 (en) | 1989-11-22 |
NO894651L NO894651L (en) | 1990-05-25 |
NO172342B true NO172342B (en) | 1993-03-29 |
NO172342C NO172342C (en) | 1993-07-07 |
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NO894651A NO172342C (en) | 1988-11-23 | 1989-11-22 | PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -DETIC ACID AND ITS DIHYDROCHLORIDE, AND INTERMEDIATE PRODUCT FOR USE BY FRAME |
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KR (1) | KR970009728B1 (en) |
AT (1) | AT398971B (en) |
CA (1) | CA1317300C (en) |
CY (1) | CY1671A (en) |
DK (1) | DK174543B1 (en) |
ES (1) | ES2021907A6 (en) |
FI (1) | FI91862C (en) |
GB (2) | GB8827391D0 (en) |
GR (1) | GR1000553B (en) |
HK (1) | HK95892A (en) |
HU (1) | HU205094B (en) |
NO (1) | NO172342C (en) |
PH (1) | PH25982A (en) |
PL (1) | PL161379B1 (en) |
PT (1) | PT92364B (en) |
SG (1) | SG89492G (en) |
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WO1994006429A1 (en) * | 1992-09-24 | 1994-03-31 | Sepracor, Inc. | Compositions for treating allergic disorders using (-) cetirizine |
GB9305282D0 (en) * | 1993-03-15 | 1993-05-05 | Ucb Sa | Enantiomers of 1-(4-chlorophenyl)phenylmethyl)-4-(4-methylphenyl)sulphonyl)piperazine |
US6469009B1 (en) | 1996-04-08 | 2002-10-22 | Ucb, S.A. | Pharmaceutical compositions for the treatment of rhinitis |
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. |
BE1010094A3 (en) * | 1996-04-10 | 1997-12-02 | Ucb Sa | NEW [2- (1-piperazinyl) ethoxy] SUBSTITUTED. |
AU7455798A (en) | 1997-06-04 | 1998-12-21 | Nippon Shoji Kaisha, Ltd. | Process for producing piperazinesulfonamide derivatives and salts thereof |
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 |
GR990100135A (en) * | 1999-04-22 | 2000-12-29 | Genepharm �.�. | Method of preparation 2-(2-{4-[(4-chlorophenyl)(phenyl)methhyl]piperasine}-ethoxy)acetic acid and its bihydrochloric salt |
JP2002249487A (en) * | 2001-02-22 | 2002-09-06 | Sumitomo Chem Co Ltd | 4-(tert-butoxycarbonyl)piperazine derivative, optically active acid addition salt of the same, method for producing them and optically active 1-[(substituted phenyl)phenylmethylpiperazine which uses them |
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EA012575B1 (en) * | 2005-03-03 | 2009-10-30 | Юсб Фархим Са | Pyroglutamate salts and their use in the optical resolution of intermediates for the synthesis of dextrocetirizine and levocetirizine |
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WO2008152650A1 (en) | 2007-06-15 | 2008-12-18 | Symed Labs Limited | Process for preparation of substantially optically pure levorotatory and dextrorotatory enantiomers of cetirizine using novel intermediates |
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CN111205247B (en) * | 2020-04-22 | 2020-08-14 | 湖南九典宏阳制药有限公司 | Preparation method of levocetirizine |
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DK154078C (en) * | 1981-02-06 | 1989-05-22 | Ucb Sa | METHOD OF ANALOGUE FOR THE PREPARATION OF 2- (2- (4- (DIPHENYL-METHYL) -1-PIPERAZINYL) ETHOXY) -ACETAMIDES OR ACID ADDITION SALTS. |
-
1988
- 1988-11-23 GB GB888827391A patent/GB8827391D0/en active Pending
-
1989
- 1989-09-29 CA CA000614709A patent/CA1317300C/en not_active Expired - Fee Related
- 1989-11-20 GR GR890100770A patent/GR1000553B/en not_active IP Right Cessation
- 1989-11-21 PT PT92364A patent/PT92364B/en not_active IP Right Cessation
- 1989-11-21 GB GB8926243A patent/GB2225321B/en not_active Expired - Lifetime
- 1989-11-22 DK DK198905867A patent/DK174543B1/en not_active IP Right Cessation
- 1989-11-22 PL PL1989282410A patent/PL161379B1/en unknown
- 1989-11-22 ES ES8903975A patent/ES2021907A6/en not_active Expired - Lifetime
- 1989-11-22 AT AT0266589A patent/AT398971B/en not_active IP Right Cessation
- 1989-11-22 NO NO894651A patent/NO172342C/en not_active IP Right Cessation
- 1989-11-22 FI FI895564A patent/FI91862C/en not_active IP Right Cessation
- 1989-11-22 HU HU896131A patent/HU205094B/en not_active IP Right Cessation
- 1989-11-23 KR KR1019890017040A patent/KR970009728B1/en not_active IP Right Cessation
- 1989-11-23 PH PH39570A patent/PH25982A/en unknown
-
1992
- 1992-09-05 SG SG894/92A patent/SG89492G/en unknown
- 1992-12-03 HK HK958/92A patent/HK95892A/en not_active IP Right Cessation
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1993
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Also Published As
Publication number | Publication date |
---|---|
ATA266589A (en) | 1994-07-15 |
PT92364A (en) | 1990-05-31 |
FI895564A0 (en) | 1989-11-22 |
GR1000553B (en) | 1992-08-26 |
DK174543B1 (en) | 2003-05-19 |
PT92364B (en) | 1995-07-18 |
PH25982A (en) | 1992-01-13 |
ES2021907A6 (en) | 1991-11-16 |
NO894651D0 (en) | 1989-11-22 |
GB8827391D0 (en) | 1988-12-29 |
HU896131D0 (en) | 1990-02-28 |
CA1317300C (en) | 1993-05-04 |
NO172342C (en) | 1993-07-07 |
HUT53627A (en) | 1990-11-28 |
SG89492G (en) | 1992-12-04 |
DK586789D0 (en) | 1989-11-22 |
NO894651L (en) | 1990-05-25 |
HK95892A (en) | 1992-12-11 |
GB2225321A (en) | 1990-05-30 |
FI91862B (en) | 1994-05-13 |
GR890100770A (en) | 1990-12-31 |
PL161379B1 (en) | 1993-06-30 |
DK586789A (en) | 1990-05-24 |
GB8926243D0 (en) | 1990-01-10 |
KR970009728B1 (en) | 1997-06-17 |
KR900007825A (en) | 1990-06-02 |
FI91862C (en) | 1994-08-25 |
AT398971B (en) | 1995-02-27 |
CY1671A (en) | 1993-05-14 |
GB2225321B (en) | 1992-04-08 |
HU205094B (en) | 1992-03-30 |
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