DK174543B1 - Process for the preparation of 2- [2- [4 - [[((4-chlorophenyl) phenylmethyl)] - 1-piperazinyl] ethoxy] acetic acid and its dihydrochloride and starting compound for use in the process - Google Patents
Process for the preparation of 2- [2- [4 - [[((4-chlorophenyl) phenylmethyl)] - 1-piperazinyl] ethoxy] acetic acid and its dihydrochloride and starting compound for use in the process Download PDFInfo
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- DK174543B1 DK174543B1 DK198905867A DK586789A DK174543B1 DK 174543 B1 DK174543 B1 DK 174543B1 DK 198905867 A DK198905867 A DK 198905867A DK 586789 A DK586789 A DK 586789A DK 174543 B1 DK174543 B1 DK 174543B1
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- phenylmethyl
- chlorophenyl
- piperazinyl
- ethoxy
- dihydrochloride
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- 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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Description
DK 174543 B1 iDK 174543 B1 i
Den foreliggende opfindelse angår en hidtil u-kendt fremgangsmåde til fremstilling af 2-[2-[4-[(4-chloropheny1)phenylmethy1]-1-piperaziny1]ethoxy]-eddikesyre med formlen /^\ clO\The present invention relates to a novel process for the preparation of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid of the formula
CH-N N-(CH.),-O-CH,C00HCH-N N- (CH.), - O-CH, C00H
\^J LZ 1 d hvori * viser molekylets asymmetriske centrum, og dens dihydrochlorid.J LZ 1 d wherein * shows the asymmetric center of the molecule and its dihydrochloride.
j Forbindelsen med formlen I kan forekommme i den venstredrej ende form, den højredrejende form eller en 15 blanding af de venstre- og højredrejende former.The compound of formula I may be present in the left-hand end, right-hand form, or a mixture of the left and right-hand forms.
Dihydrochloridet 2-[2-[4-[(4-chlorophenyl)- phenylmethyl]-l-piperazinyl]-eddikesyre, hvilket også kendes ved det generiske navn cetirizin, er fornylig introduceret som et nyt medikament til behandling af 20 allergiske syndromer, såsom kronisk eller akut aller gisk rhinitis, allergisk conjunctivitis, pruritus, urticaria osv.The dihydrochloride 2- [2- [4 - [(4-chlorophenyl) - phenylmethyl] -1-piperazinyl] -acetic acid, also known by the generic name cetirizine, has recently been introduced as a new drug for the treatment of 20 allergic syndromes, such as chronic or acute very acute rhinitis, allergic conjunctivitis, pruritus, urticaria, etc.
I europæisk patentskrift Nr. 58,146 i samme navn som nærværende ansøgning beskrives en fremgangsmåde til 25 fremstilling af 2-[2-[4-[(4-chlorophenyl)phenyl- methyl]-l-piperazinyl]-eddikesyre og dens dihydrochlorid. ved denne fremgangsmåde er udgangsmaterialet 1-[(4-chlorophenyl)phenylmethylj-piperazin, der omsættes med methyl-(2-chlorethoxy)-acetat til opnåelse af - 30 methyl-2-[2-[4-[(4-chlorphenyl)phenylmethyl]-l-pipera- zinyl]ethoxy]-acetat i et udbytte på 27,8%. Denne me-thylester underkastes dernæst hydrolyse med en uorganisk base (natrium- eller kaliumhydroxid) til opnåelse 35 2 DK 174543 B1 af natrium- eller kaliumsaltet, som let omdannes til en fri syre og dernæst til cetirizin-dihydrochlorid.In European patent no. 58,146 in the same name as the present application discloses a process for the preparation of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] acetic acid and its dihydrochloride. in this process, the starting material is 1 - [(4-chlorophenyl) phenylmethyl] -piperazine which is reacted with methyl (2-chloroethoxy) acetate to give - methyl-2- [2- [4 - [(4-chlorophenyl)] phenylmethyl] -1-piperazinyl] ethoxy] acetate in a yield of 27.8%. This methyl ester is then subjected to hydrolysis with an inorganic base (sodium or potassium hydroxide) to give the sodium or potassium salt, which is readily converted to a free acid and then to cetirizine dihydrochloride.
Den væsentligste ulempe ved denne fremgangsmåde er, at det samlede udbytte af 2-[2-[4-[(4-chlorphe-5 ny1)phenylmethyl]-l-piperaz inyl]ethoxy]edd ikesyre-di-hydrochlorid kun er 10,6% på basis af den anvendte mængde l-[(4-chlorphenyl)-phenylmethyl]-piperazin.The major disadvantage of this process is that the total yield of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride is only 10, 6% based on the amount of 1 - [(4-chlorophenyl) -phenylmethyl] -piperazine used.
Ifølge den foreliggende opfindelse tilvejebringes en hidtil ukendt fremgangsmåde, der muliggør opnå-10 else af 2-[2-[4-[(4-chlorphenyl)phenylmethyl]-l-pipera-zinyl]ethoxy]eddikesyre og dens dihydrochlorid med bedre udbytter.According to the present invention, there is provided a novel process which allows the obtaining of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride with better yields.
Ifølge den foreliggende opfindelse fremstilles 2-[2-[4-[(4-chlorphenyl)phenylmethyl]-l-piperazinyl] 15 ethoxy]eddikesyre med formlen n CH-N^ ^N-(CH2)2-O-CH2-C00H (i) d og dens dihydrochlorid ved en fremgangsmåde, der er ejendommelig ved, at 2-[2-[4-[(4-chlorphenyl)phenylmethyl] -l-piperazinyl] -ethoxy ]acetonitril med formlen 25According to the present invention, 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid of the formula n is CH-N 2 N- (CH 2) 2 -O-CH 2 -C (i) d and its dihydrochloride by a process characterized in that 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile of formula 25
clVAclVA
\ / \ , 7 - '\ / \, 7 - '
CK-N N-(CK2)2-0-CH2-Cii “iJCK-N N- (CK2) 2-0-CH2-Cii
» ύ' hydrolyseres i et vandigt, alkoholisk eller vandigt-alkoholisk medium med en base eller en syre, og at den således opnåede syre med formlen I om ønsket omdannes til dens dihydrochlorid.'Ύ' is hydrolyzed in an aqueous, alcoholic or aqueous-alcoholic medium with a base or an acid, and the acid of formula I thus obtained is converted to its dihydrochloride if desired.
3 DK 174543 B13 DK 174543 B1
Opfindelsen angår også 2-[2-[4-[(4-chlorphenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitril med formlen II der anvendes som udgangsmateriale og er en hidtil ukendt forbindelse, der let opnås ved omsætning 5 af l-[(4-chlorphenyl)phenylmethyl] piperazin med formlen III med 2-halogenethoxyacetonitril med formlen IV efter reaktionsllgnlnoen: C‘^A nThe invention also relates to 2- [2- [4 - [(4-chlorophenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetonitrile of formula II used as starting material and is a novel compound readily obtained by reaction 5 of 1 - [(4-chlorophenyl) phenylmethyl] piperazine of formula III with 2-haloethoxyacetonitrile of formula IV after the reaction: C
10 CH-N^_^N.H10 CH-N ^ _ ^ N.H
rzr^J X-(CH2)z-Q-CH2-CNrzr ^ J X- (CH2) z-Q-CH2-CN
<m·. a/=\ <IV><M ·. and / = \ <IV>
H /-NH / -N
ις CH-W H-(CE,J,-0-CE -CSις CH-W H- (CE, J, -0-CE -CS
15 . N_t 2 2 Z15. N_t 2 2 Z
o hvor, X betegner et halogenatom.where X represents a halogen atom.
Denne reaktion udføres i et indifferent, orga- 20 nisk opløsningsmiddel såsom en alkohol (f.eks. n-buta-nol, osv), i tilstedeværelse af en syreacceptor, såsom et alkalimetalcarbonat og evt. i tilstedeværelse af en lille mængde alkalimetaliodid til acceleration af reaktionen, fortrinsvis ved en temperatur nær ved tilbage-svalingstemperaturen.This reaction is carried out in an inert organic solvent such as an alcohol (e.g. n-butanol, etc.), in the presence of an acid acceptor such as an alkali metal carbonate and optionally in the presence of a small amount of alkali metal iodide to accelerate the reaction, preferably at a temperature close to the reflux temperature.
Ved anvendelse af en optisk aktiv l-[(4-chlor-phenyl)phenylmethyl]-piperazin med formlen III i stedet for racematet ved denne reaktion kan udgangsenantiome-ren opnås ved adskillelse af den tilsvarende racemiske 30 forbindelse i de optisk aktive enantiomere ved fremgangsmåder, der er kendte i sig selv.Using an optically active 1- [(4-chloro-phenyl) phenylmethyl] -piperazine of formula III instead of the racemate in this reaction, the starting enantiomer can be obtained by separating the corresponding racemic compound into the optically active enantiomers by methods that are known per se.
Af de optisk aktive syrer, der kan anvendes til denne adskillelse, foretrækkes vinsyre.Of the optically active acids which can be used for this separation, tartaric acid is preferred.
4 DK 174543 B14 DK 174543 B1
Med hensyn til 2-halogenethoxyacetonitrilerne med formlen IV og især 2-chlorethoxyacetonitril, kan disse forbindelser fremstilles efter fremgangsmåden beskrevet af E.J. SALMI et al., Suomen Kemistilehti, 5 17B, (1944), 17-19 (Chem. Abstr. 40 (1946), 6491).With respect to the 2-haloethoxyacetonitriles of Formula IV and especially 2-chloroethoxyacetonitrile, these compounds can be prepared according to the method described by E.J. SALMI et al., Suomen Chemistilehti, 5 17B, (1944), 17-19 (Chem. Abstr. 40 (1946), 6491).
2-[2-[4-[(4-chlorphenyl)phenylmethyl]-1-pipera-zinyl]ethoxy]eddikesyren med formlen I opnås ved hydrolyse af 2-[2-[4-[(4-chlorphenyl)phenylmethyl]-l-pipera-zinyl]ethoxy]-acetonitril med formlen II efter reak-10 tionsligningen: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 formula II after the reaction equation:
01 xljA01 xljA
\ / \ CH-N N-(CH-),-0-CH_-CN -> , v_/ 2 2 2 O7 '—' (II)\ / \ CH-N N- (CH -), - 0-CH_-CN ->, v_ / 2 2 2 O7 '-' (II)
Denne hydrolyse kan udføres ved to fremgangsmåder, den ene i basisk medium og den anden I surt medium.This hydrolysis can be carried out by two methods, one in basic medium and the other in acidic medium.
20 i. Hydrolyse af nitrilet 1 basisk medium20 i. Hydrolysis of the nitrile 1 basic medium
Nitrilet med formlen II opvarmes ved tilstedeværelse af en uorganisk base, såsom et alkalimetalhy-droxld, i et vandig, alkoholisk eller vandig-alkoholisk 25 medium (methanol, ethanol, osv.) ved en temperatur mellem 60°C og reaktionsblandingens tilbagesvalingstemperatur.The nitrile of formula II is heated in the presence of an inorganic base such as 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 formlen I er til stede i reaktionsblandingen i form af dens alkalimetalsalt, ud fra hvilket syren frigives ved surgøring af reaktionsblandingen ved hjælp af en uorganisk syre (såsom saltsyre). Syren med formlen I ekstraheres dernæst ved hjælp af et organisk opløsningsmiddel (dichlormethan, 35 5 DK 174543 B1 toluen osv.) og krystalliseres til isolation. Endelig omdannes syren med formlen I til dihydrochloridet ved en fremgangsmåde, der er i sig selv kendt.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 released by acidification of the reaction mixture by an inorganic acid (such as hydrochloric acid). The acid of formula I is then extracted by an organic solvent (dichloromethane, toluene, etc.) and crystallized for isolation. Finally, the acid of formula I is converted to the dihydrochloride by a method known per se.
5 2. Hydrolyse af nitrllet 1 et surt medium2. Hydrolysis of the nitrile in an acidic medium
Nitrilet med formlen II opvarmes i tilstedeværelse af en uorganisk syre, såsom saltsyre, fortrinsvis i et vandigt medium ved en temperatur på mellem 60 C og 10 reaktionsblandingens tilbagesvalingstemperatur. Den dannede syre med formlen I ekstraheres dernæst fra reaktionsblandingen ved hjælp af et organisk opløsningsmiddel (dichlormethan, toluen osv.) og renses ved krystallisation. Den frie syre med formlen I omdannes der-15 næst til dihydrochloridet ved en i sig selv kendt fremgangsmåde. Denne nye fremgangsmåde giver udbytter af cetirizin-dihydrochlorid beregnet i forhold til den anvendte mængde l-[(4-chlorphenyl)phenylmethyl]pipera-zin på 60% eller mere ved sur hydrolyse og 65% eller 20 ved basisk hydrolyse. Endvidere kan meget høje udbytter af de optisk aktive former af denne forbindelse opnås ved denne fremgangsmåde. Disse høje udbytter ud fra l-[(4-chlorphenyl)phenylmethyl]-piperazin udgør et væsentligt teknisk fremskridt i forhold til fremgangsmå-25 den beskrevet i europæisk patentskrift nr. 58,146.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 of between 60 ° C and the reflux temperature of the reaction mixture. The acid of formula I formed is then extracted from the reaction mixture by an organic solvent (dichloromethane, toluene, etc.) and purified by crystallization. The free acid of formula I is then converted to the dihydrochloride by a method known per se. This new process yields yields of cetirizine dihydrochloride calculated from the amount of 1 - [(4-chlorophenyl) phenylmethyl] piperazine of 60% or more in acid hydrolysis and 65% or 20 in basic hydrolysis. Furthermore, very high yields of the optically active forms of this compound can be obtained by this method. These high yields from 1 - [(4-chlorophenyl) phenylmethyl] -piperazine represent a significant technical advance over the process described in European Patent No. 58,146.
I det følgende gives eksempler til nærmere belysning af opfindelsen.Examples are given in the following to illustrate the invention.
30 DK 174543 B1 630 DK 174543 B1 6
Eksempel lExample 1
Fremstilling af racemlsk 2-Γ2-Γ4-Γ(4-chlorphenyl) phenylmethyl]-1-plperazlnyl]ethoxy 1eddlkesyre-5 dihydrochlorld med formlen IPreparation of racemic 2-Γ2-Γ4-Γ (4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy-1-acetic acid dihydrochloride of formula I
1. Racemlsk 2-f2-[4-[(4-chlorphenyl)phenylmethyll-1. Racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl]
1-plperazlnyllethoxyT-acetonitrll med formel II1-piperazinylethoxyT-acetonitrile of formula II
10 200 ml n-butanol, 43,05 g (0,15 mol) racemlsk l-[(4-chlorphenyl)phenylmethyl]-piperazln], 24 g (0,174 mol) 2-chlorethoxyacetonitril, 26,1 g (0,246 mol) natriumcarbonat og 0,78 g (0,0047 mol) kaliumiod-ld indføres successivt 1 en trehalset, rundbundet kolbe 15 forsynet med en mekanisk omrører, en svaler og et termometer. Blandingen opvarmes ved 110°C i il timer under omrøring, afkøles, filtreres og koncentreres på en ro-tationsinddamper. 60 g af en gulbrun olie isoleres og chromatograferes over en kolonne indeholdende 1 kg si-20 lica under anvendelse af en blanding, der på basis af volumen indeholder 98% dichlormethan og 2% methanol.200 ml of n-butanol, 43.05 g (0.15 mol) of racemic 1 - [(4-chlorophenyl) phenylmethyl] -piperazine], 24 g (0.174 mol) of 2-chloroethoxyacetonitrile, 26.1 g (0.246 mol) sodium carbonate and 0.78 g (0.0047 mole) of potassium iodine are successively introduced into a three-necked, round-bottom flask equipped with a mechanical stirrer, a swallower and a thermometer. The mixture is heated at 110 ° C for 1 hour with stirring, cooled, filtered and concentrated on a rotary evaporator. 60 g of a tan oil are isolated and chromatographed over a column containing 1 kg of silica using a volume-based mixture containing 98% dichloromethane and 2% methanol.
Det ønskede nitril opsamles i to fraktioner, hvorfra opløsningsmidlerne fjernes, og renheden måles ved hplc.The desired nitrile is collected in two fractions from which the solvents are removed and the purity is measured at hplc.
Racemlsk 2—[2—[4—[(4-chlorphenyl)phenylmethyl]-25 l-piperazinyl]ethoxy]acetonitril opnås således i to fraktioner, en på 33,6 g med en renhed på 100% og en anden på 14,4 g med en renhed på 97,4%.Thus racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -25-piperazinyl] ethoxy] acetonitrile is obtained in two fractions, one of 33.6 g with a purity of 100% and another of 14, 4 g with a purity of 97.4%.
Udbytte: 86,4%.Yield: 86.4%.
Det opnåede produkt kan karakteriseres i form af 30 dets dihydrochlorid fremstillet ud fra en ethanolopløs-ning af gasformig hydrogenchlorid.The product obtained can be characterized in the form of its dihydrochloride prepared from an ethanol solution of gaseous hydrogen chloride.
Smp. 201-202°C.Mp. 201-202 ° C.
DK 174543 B1 7DK 174543 B1 7
Analyse for C2jH24ClN3.0,2HCl i %Analysis for C₂jH₂ClClN3.0.2HCl in%
Beregnet: C 56,96 H 5,91 N 9,48 Cl" 16,01 Cltot‘24,02 Fundet: C 57,21 H 6,00 N 9,49 Cl" 15,78 Cltot*23,76 5 2. Racemisk 2-Γ2-Γ4-Γ(4-chlorphenyl)phenylmethyl1-l-pl- perazlnyl]ethoxy1eddikesyre med formlen I (ved hydrolyse 1 basisk medium) 250 ml ethanol, 23 g (0,062 mol) racemisk 2-(2-10 [4-[(4-chlorphenyl)phenylmethyl]-l-piperazinyl]ethoxy] acetonitril og 31 ml af en 4N ethanolopløsning af kaliumhydroxid indføres successivt i en trehalset, rund-bundet kolbe forsynet med en mekanisk omrører, en svaler og et termometer. Reaktionsblandingen opvarmes un-15 der tilbagesvaling i 10 timer under omrøring. Reaktionsblandingen lades afkøle, og dens pH værdi indstilles på 6 ved tilsætning af 37% koncentreret saltsyre. Etha-nolet afdrives, og reaktionsblanding fortyndes med 100 ml vand og extraheres 3 gange med 200 ml i dichlorme-20 than. De organiske faser forenes, tørres over Mgso4, filtreres og koncentrers i en rotationsinddamper. Der opnås en olie, som krystalliseres ved tilsætning af 100 ml 2-butanon, mens den er varm. Det dannedes faste stof filtreres fra, vaskes og tørres. Herved opnås 18,9 g 25 racemisk 2-[2-[4-[(4-chlorphenyl)phenylmethyl]-l-pipe-razinyl]ethoxy]eddikesyre.Calculated: C 56.96 H 5.91 N 9.48 Cl "16.01 Cltot 24.02 Found: C 57.21 H 6.00 N 9.49 Cl" 15.78 Cltot * 23.76 5 2 Racemic 2- [2- [4- (4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxyacetic acid of Formula I (by hydrolysis 1 basic medium) 250 ml of ethanol, 23 g (0.062 mol) of racemic 2- (2-10 [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile and 31 ml of a 4N potassium hydroxide ethanol solution are successively introduced into a three-necked, round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The reaction mixture is heated to reflux for 10 hours with stirring, the reaction mixture is allowed to cool and its pH is adjusted 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 3 times with 200 ml. The organic phases are combined, dried over MgSO 4, filtered and concentrated in a rotary evaporator to give an oil which is crystallized by addition of 100 ml of 2-butanone while warm. The solid formed is filtered off, washed and dried. There is thus obtained 18.9 g of racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-pipe-razinyl] ethoxy] acetic acid.
18,9 g af den opnåede syre resuspenderes i 150 ml vand, og pH værdien indstilles til 0,8 ved tilsætning af koncentreret saltsyre. Den vandige opløsning 30 koncentreres på en rotationsinddamper, og remanensen fortyndes dernæst ved tilsætning af 75 ml 2-butanon, hvorefter der koncentreres igen. Tilsætning af 150 ml 2-butanon til den således opnåede remanens fremkalder DK 174543 B1 e krystallisation af racemisk 2-[2-[4-[(4-chlorphenyl)-phenylmethyl]-1-piperazinyl]ethoxy]eddikesyre-dihy-drochlorid. Krystallerne filtreres fra og tørres til opnåelse af 21,7 g.18.9 g of the acid obtained is resuspended in 150 ml of water and the pH is adjusted to 0.8 by the addition of concentrated hydrochloric acid. The aqueous solution 30 is concentrated on a rotary evaporator and the residue is then diluted by the addition of 75 ml of 2-butanone and then concentrated again. Addition of 150 ml of 2-butanone to the residue thus obtained induces the crystallization of racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride. The crystals are filtered off and dried to give 21.7 g.
5 Udbytte: 75,9%. Smp. 220,15°C (differentialscannings-kaiorimetri, DSC) (decomponering ved smeltning)Yield: 75.9%. Mp. 220.15 ° C (differential scanning quayimetry, DSC) (decomposition by melting)
Analyse for C2iH25clN2°3 *2HC3· i % 10 Beregnet calcium: C 54,56 H 5,84 N 6,06 Cl" 15,37 Cltot· 23,05 Fundet : C 54,60 H 5,86 N 6,02 Cl" 15,33 Cltot* 23,26Calcd: C 54.56 H 5.84 N 6.06 Cl - 15.37 Cltot · 23.05 Found: C 54.60 H 5.86 N 6.02 Cl "15.33 Cltot * 23.26
Det samlede udbytte af di-hydrochloridet 2-[2-[4-[(4-13 chlorphenyl)phenylmethyl]-l-piperazinyl]ethoxy]eddikesyre beregnet i forhold til den anvendte mængde i-[(4-chlorphenyl)phenylmethyl]piperazin af 65,6%.The total yield of the di-hydrochloride 2- [2- [4 - [(4-13 chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid calculated in relation to the amount of use in - [(4-chlorophenyl) phenylmethyl] piperazine of 65.6%.
3. Racemisk 2—f2— Γ4— Γ(4-chlorphenyl)phenylmethyl]-1-pi-20 perazlnyliethoxyleddikesyre med formel I (ved hydrolyse i surt medium) 45,3 g (0,123 mol) racemisk 2-[2-[4-[(4-chlorphenyl )phenylmethyl]-1-piperazinylJethoxy]-acetonitril 25 indføres i en reaktor udstyret med en mekanisk omrører en svaler, et termometer og en tildrypningstrakt og opvarmes til 45 C under omrøring. 41 ml 37% koncentreret saltsyre tilsættes dernæst dråbevis. Reaktionsblandingens temperatur hæves til 92°C. Reaktionsblandingen op-30 varmes ved 95°C i 90 minutter under omrøring. Reak-tionsblandigen lades afkøle og koncentreres på en rotationsinddamper, remanensen kommes i 150 ml toluen, og reaktionsblandingen koncentreres igen på en rotations- DK 174543 B1 9 inddamper. Remanensen opløses i 200 ml vand, og den opnåede vandige opløsning indstilles til en pH-værdi på 5 ved tilsætning af natriumhydroxid. Opløsningen eks-traheres 3 gange med 300 ml dichlormethan. De organiske 5 faser kombineres, opløsningsmidlet fjernes på en rotationsinddamper. Den således opnåede olie lades krystallisere ved dipergering i 250 ml 2-butanon, mens den er varm.3. Racemic 2- (2-4 - (4-chlorophenyl) phenylmethyl] -1-piperazinylethoxylacetic acid of Formula I (by hydrolysis in acidic medium) 45.3 g (0.123 mol) of racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinylethoxy] -acetonitrile 25 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. 41 ml of 37% concentrated hydrochloric acid are then added dropwise. The temperature of the reaction mixture is raised to 92 ° C. The reaction mixture is heated at 95 ° C for 90 minutes with stirring. The reaction mixture is allowed to cool and concentrated on a rotary evaporator, the residue is added to 150 ml of toluene and the reaction mixture is again concentrated on a rotary evaporator. The residue is dissolved in 200 ml of water and the obtained aqueous solution is adjusted to a pH of 5 by the addition of sodium hydroxide. The solution is extracted 3 times with 300 ml of dichloromethane. The organic phases are combined, the solvent removed on a rotary evaporator. The oil thus obtained is allowed to crystallize by dipping into 250 ml of 2-butanone while hot.
Blandingen afkøles og filtreres, og krystallerne 10 tørres. 34 g racemisk 2-[2-[4-[(4-chlorphenyljphenylme-thyl]-l-piperazinyl]ethoxy]eddikesyre isoleres herved.The mixture is cooled and filtered and the crystals 10 are dried. 34 g of racemic 2- [2- [4 - [(4-chlorophenyl] phenylmethyl] -1-piperazinyl] ethoxy] acetic acid are hereby isolated.
34 g af den således opnåede syre resuspenderes i 300 ml vand. pH værdien indstilles til 0,8 ved tilsætning af koncentreret saltsyre. Den vandige opløsning koncentre-15 res på en rotationsinddamper, remanensen fortyndes ved tilsætning af 150 ml 2-butanon, og blandingen koncentreres igen. Tilsætnig af 300 ml 2-butanon til den således opnåede remanens giver krystallisation af racemisk 2-[2-[4-[(4-chlorphenyl)phenylmethyl]-i-piperazi-20 nyl]ethoxy]eddikesyre-dihydrochlorid. Krystallerne filtreres fra og tørres til opnåelse af 39,7 g krystaller. Udbytte: 70%. Smp: 227,02°C (DSC) (dekomponering ved smeltning).34 g of the acid thus obtained is resuspended in 300 ml of water. The pH is adjusted to 0.8 by the addition of concentrated hydrochloric acid. The aqueous solution is concentrated on a rotary evaporator, the residue is diluted by the addition of 150 ml of 2-butanone and the mixture is concentrated again. Addition of 300 ml of 2-butanone to the residue thus obtained gives crystallization of racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride. The crystals are filtered off and dried to give 39.7 g of crystals. Yield: 70%. Mp: 227.02 ° C (DSC) (decomposition upon melting).
25 Analyse for C21H25C1N2°3*2HC1 1 %Analysis for C 21 H 25 ClN 2 O 3 * 2HCl 1%
Beregnet: c 54,56 H 5,84 N 6,06 Cl" 15,37 Cltot* 23,05 Fundet: C 54,30 H 5,88 N 6,83 Cl" 15,56 Cltot. 23,06Calculated: c 54.56 H 5.84 N 6.06 Cl "15.37 Cltot * 23.05 Found: C 54.30 H 5.88 N 6.83 Cl" 15.56 Cltot. 23.06
Det samlede udbytte af 2-[2-[4-[(4-chlorphenyl)phenyl-30 methyl]-l-piperazlnyl]ethoxy]eddikesyre-dihydrochlorid, beregnet i forhold til den anvendte mængde l-[4-chlorphenyl )phenylmethyl]-piperazin, er 60,5%.The total yield of 2- [2- [4 - [(4-chlorophenyl) phenyl-methyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride, calculated from the amount of 1- [4-chlorophenyl) phenylmethyl] -piperazine, is 60.5%.
i I DK 174543 B1 10i I DK 174543 B1 10
Eksempel 2Example 2
Fremstilling af højredre1ende 2-Γ2-Γ4-Γ(4-chlor- j phenyl)phenylmethyl1-l-plperazlnyl]ethoxy 1eddlkesy-Preparation of right-turn 2-Γ2-Γ4-Γ (4-chloro-phenyl) -phenylmethyl-1-p-piperazinyl] -ethoxy-1
5 re-dlhydrochlorld med formlen I5 hydrochloride of formula I
1. Venstredrej ende 1-f(4-chlorphenyl)phenylmethyl]-plperazln med formlen III1. Left end 1 - [(4-chlorophenyl) phenylmethyl] -plperazine of formula III
10 En opløsning af 300 g (2 mol) (2R, 3R)-vinsyre i 2 liter ethanol opvarmes ved 72-74°C og en opløsning af 206,5 g (1 mol) racemisk l-[(4-chlorphenyl)phenylmethyl) -piperazine i 1 liter ethanol tilsættes under omrøring. Blandingen tilbagesvales i 5 minutter og lades 15 dernæst afkøle til stuetemperatur under omrøring (det , ønskede salt begynder at krystallisere ved ca. 57°C).A solution of 300 g (2 mole) (2R, 3R) tartaric acid in 2 liters of ethanol is heated at 72-74 ° C and a solution of 206.5 g (1 mole) of racemic 1 - [(4-chlorophenyl) phenylmethyl ) -piperazine in 1 liter of ethanol is 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 at about 57 ° C).
Det opnåede salt filtreres fra og omkrystalliseres 3 gange efter hinanden, først af en blanding af 2 liter ethanol og 0,8 1 methanol, dernæst af l liter ethanol 20 og endelig af en blanding af 0,5 liter ethanol, 65 ml methanol og 5 ml vand. Efter filtrering og tørring opnås 118 g diastereoisomerisk urent l-[(4-chlorphenyl) phenylmethyl]-piperazin (2R, 3R)-tartrat.The obtained salt is filtered off and recrystallized 3 times in succession, first by a mixture of 2 liters of ethanol and 0.8 liters of methanol, then by 1 liter of ethanol 20 and finally by a mixture of 0.5 liters of ethanol, 65 ml of methanol and 5 ml of water. After filtration and drying, 118 g of diastereoisomeric crude 1 - [(4-chlorophenyl) phenylmethyl] -piperazine (2R, 3R) tartrate is obtained.
Smp.: 170,4*0 (DSC), [a]25 : + 7,8°C (c = l, methanol).Mp: 170.4 ° C (DSC), [α] 25: + 7.8 ° C (c = 1, methanol).
25 Dette salt sønderdeles dernæst ved tilsætning af en opløsning af 22 g (0,55 mol) natriumhydroxid i 750 ml vand. Det således opnåede venstredrejede l-[(4-chlor phenyl)phenylmethyl]-piperazin ekstraheres adskillige gange med dichlormethan. De forenede organiske faser 30 tørres over natriumsulfat, filtreres og koncentreres på en rotationsinddamper. 80 g optisk urent venstredrej ende l-[(4-chlorphenyl)phenylmethyl]-piperazin opnås.This salt is then decomposed by adding a solution of 22 g (0.55 mol) of sodium hydroxide in 750 ml of water. The thus obtained left-turn 1 - [(4-chloro-phenyl) -phenylmethyl] -piperazine is extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated on a rotary evaporator. 80 g of optically impure left-turn l - [(4-chlorophenyl) phenylmethyl] -piperazine are obtained.
Dette produkt renses ved gentagne omkrystallisationer DK 174543 B1 11 af hexan til opnåelse af 18,2 g venstredrejende l-[(4-chlorphenyl)phenylmethyl]-piperazin.This product is purified by repeated recrystallizations of hexane to give 18.2 g of left-turn l - [(4-chlorophenyl) phenylmethyl] -piperazine.
Smp.: 90-92°C. Smp.: 90,35*0 (DSC) [a]25 : -19,4*· j (c = 1, toluen).Mp: 90-92 ° C. Mp: 90.35 ° (DSC) [α] 25: -19.4 ° · j (c = 1, toluene).
1 . 5 Udbytte: 12,7%.1. Yield: 12.7%.
2. venstredrej ende 2-Γ2-Γ4-Γ(4-chlorphenyl)phenylmethyl 1-1-plperazinyllethoxyT-acetonitrll med formlen II2nd left end 2-Γ2-Γ4-Γ (4-chlorophenyl) phenylmethyl 1-1-piperazinylethoxyT-acetonitrile of formula II
10 100 ml n-butanol, 20 g (0,07 mol) venstredrej en de l-[(4-chlorphenyl)phenylmethyl]-piperazin, 11,2 g (0,0937 mol) 2-chlorethoxyacetonitril, 12,18 g (0,115 mol) natriumcarbonat og 0,36 g (0,002 mol) kaliumiodid indføres successivt i en trehalset, rundbundet kolbe, 15 forsynet med en mekanisk omrører, en svaler og et ter- 0 mometer. Blandingen opvarmes ved 110 C i 7 timer under omrøring, hvorefter den afkøles, filtreres, og koncentreres på en rotationsinddamper. 26 g af en gulbrun olie isoleres og chromatograferes over en kolonne inde-20 holdende l kg silica under anvendelse af en blanding der på basis af volumen indeholder 98% dichlormethan og 2% methanol. 17,8 g venstredrej ende 2-[2-[4-[(4-chlorphenyl )phenylmethyl]-1-piperaz inyl]ethoxy]-acetonitril opnås i form af en olie.100 ml of n-butanol, 20 g (0.07 mol) of left-turn and the 1 - [(4-chlorophenyl) phenylmethyl] -piperazine, 11.2 g (0.0937 mol) of 2-chloroethoxyacetonitrile, 12.18 g ( 0.115 mole) of sodium carbonate and 0.36 g (0.002 mole) of potassium iodide are successively introduced into a three-necked, round-bottom flask, provided with a mechanical stirrer, a swallower and a thermometer. The mixture is heated at 110 ° C for 7 hours with stirring, then cooled, filtered and concentrated on a rotary evaporator. 26 g of a tan oil are isolated and chromatographed over a column containing 1 kg of silica using a volume-based mixture containing 98% dichloromethane and 2% methanol. 17.8 g of left-turn 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetonitrile are obtained in the form of an oil.
25 : -3i,8* (c “ methanol). Udbytte 69%.25: -3i, 8 * (c "methanol). Yield 69%.
Produktet kan karakteriseres i form af dets hy-drochlorid fremstillet ud fra ethanolopløsning af gas-formig hydrogenchlorid.The product can be characterized in the form of its hydrochloride prepared from ethanol solution of gaseous hydrogen chloride.
Smp.: 211-212 C [a]25 : +7,18 C (c = 1, methanol).Mp: 211-212 ° C [α] 25: +7.18 ° C (c = 1, methanol).
30 1 12 DK 174543 B130 1 12 DK 174543 B1
Analyse for C21H24ClN30/2HCl 1 %Analysis for C21H24ClN30 / 2HCl 1%
Beregnet: C 56,96 H 5,91 N 9,49 Cl" 16,01 citot* 24,02 Fundet: C 56,92 H 5,93 N 9,33 Cl" 15,76 Cltot* 23,65 5 3. Højredrej ende 2-Γ2-Γ4-f(4-chlorphenyl)phenylmethyl!-Calculated: C 56.96 H 5.91 N 9.49 Cl "16.01 quote * 24.02 Found: C 56.92 H 5.93 N 9.33 Cl" 15.76 Cltot * 23.65 5 3 Right-turn 2-Γ2-Γ4-f (4-chlorophenyl) phenylmethyl
l-plperazlnyl1 ethoxyleddlXesyre-dihvdrochlorld med formlen I1-piperazinyl1-ethoxyl-dioxylacetic acid dihydrochloride of formula I
9,42 g (0,0255 mol) venstredrej ende 2-[2-[4-[(4-10 chlorphenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetoni-tril Indføres 1 en reaktor forsynet med en mekanisk omrører, en svaler, et termometer og en tildrypningstrakt og opvarmes til 45 C under omrøring. 15 ml 37% koncentreret saltsyre tilsættes dernæst. Reaktionsblandingen 15 temperatur hæves dernæst til 92 C. Reaktionsblandingen9.42 g (0.0255 mol) of left-hand 2- [2- [4 - [(4-10 chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile Introduces into a reactor equipped with a mechanical stirrer, a swallow, a thermometer and a dropping funnel and heated to 45 ° C with stirring. 15 ml of 37% concentrated hydrochloric acid are then added. The reaction mixture temperature is then raised to 92 C. The reaction mixture
OISLAND
opvarmes ved 60 C i 60 minutter under omrøring. Reaktionsblandingen lades afkøle og koncentreres i en rotationsinddamper, og remanensen optages i 50 ml vand. Reaktionsblandingen pH-værdi indstilles til 5 ved til-20 sætning af natriumhydroxid, og blandingen ekstraheres gentagne gange med portioner af dichlormethan. De organiske faser forenes og tørres over MgS04, og opløsningsmidlet fjernes på en rotationsinddamper. Herved opnås 9,6 g af den frie syre med formlen I i form af et 25 beigefarvet pulver, og denne omdannes til dihydrochlo-ridet ved hjælp af en saltsyreopløsnig i acetone, og dihydrochloridet krystalliseres. Efter filtrering og tørring opnås 9,8 g højredrejende 2-[2-[4-[(4-chlor-phenyl)phenylmethyl]-1-piperazinyl]ethoxy]edd ikesy-30 re-dihydrochlorid. Renheden af dette produkt målt med hplc ved en chiral stationær fase af o^-AGP (fra LKB Company) er 95% med hensyn til den højredrejende enantiomer.heated at 60 ° C for 60 minutes with stirring. The reaction mixture is allowed to cool and concentrated 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 the addition of sodium hydroxide and the mixture is extracted repeatedly with portions of dichloromethane. The organic phases are combined and dried over MgSO 4 and the solvent is removed on a rotary evaporator. Thereby, 9.6 g of the free acid of formula I is obtained in the form of a beige colored powder and this is converted to the dihydrochloride by means of a hydrochloric acid solution in acetone and the dihydrochloride is crystallized. After filtration and drying, 9.8 g of right-turning 2- [2- [4 - [(4-chloro-phenyl) phenylmethyl] -1-piperazinyl] ethoxy] is obtained from acetic acid dihydrochloride. The purity of this product measured with hplc at a chiral stationary phase of o
DK 174543 B1 13DK 174543 B1 13
Smp.: 199-201°C. Smp.: 224,4°C (DSC), [a]1 2 3 4 5 6 7 8 9 10 11 : +9,4° (c = l, vand).Mp: 199-201 ° C. Mp: 224.4 ° C (DSC), [α] 1 2 3 4 5 6 7 8 9 10 11: + 9.4 ° (c = 1, water).
Analyse for c21h25c^n2°3'2Hc^· ί % 5 Beregnet: C 54,56 H 5,84 N 6,06 Cl" 15,37 Cltot· 23,05 Fundet: C 54,00 H 5,88 N 5,91 Cl" 15,55 Cltot· 23,13Analysis for C21 H25 C2 N2 O3'2Hc3 ·% 5 Calculated: C 54.56 H 5.84 N 6.06 Cl - 15.37 Cltot · 23.05 Found: C 54.00 H 5.88 N 5 , 91 Cl „15.55 Cltot · 23.13
Det samlede udbytte af højredrejende 2—[2—[4— [(4-chlorphenyl)phenylmethyl]-1-piperazinyl]ethoxy]-10 eddlkesyre-dihydrochlorid, beregnet 1 forhold til mængden af venstredrej ende i-([4-chlorphenyl-phenylmethyl]-piperazin er 57,3%The total yield of right-turning 2 - [2 - [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -10 acetic acid dihydrochloride, calculated in proportion to the amount of left-hand turn in - ([4-chlorophenyl) phenylmethyl] -piperazine is 57.3%
Eksempel 3 15Example 3 15
Fremstilling af venstredrej ende 2-Γ 2-Γ 4-[(4-chlorphenyl )phenylmethyl1-1-plperazlnyl1ethoxy 1eddlkesyre-dihydrochlorid med formlen IPreparation of Left-turn 2-Γ 2-Γ 4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy-1-acetic acid dihydrochloride of formula I
Dette produkt opnås ved fremgangsmåden beskrevet i eks 2 empel 2, men ud fra højredrejende i-[2-[4-[(4-chlorphe 3 nyl ) phenylmethyl ]-l-piperazin, som fremstilles som i 4 eksempel 2.1 ved behandling af racematet med (2S, 3S)- 5 vinsyre.This product is obtained by the method described in Example 2, but from the right-turning i- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazine, which is prepared as in Example 4 by treating the racemate with (2S, 3S) - 5 tartaric acid.
66
Det venstredrej ende syre dihydrochlorid med 7 formlen I opnås i et udbytte og med en renhed, der er 8 meget nær ved den opnåede for det højredrejende syre- 9 dihydrochlorid: 95% målt ved hplc med en chiral statio 10 nær fase af c^-AGP (fra LKB Company).The left-sided acid dihydrochloride of formula I is obtained in a yield and with a purity 8 very close to that obtained for the right-handed acid 9 dihydrochloride: 95% measured at hplc with a chiral station 10 near the phase of c AGP (from LKB Company).
1111
Smp. : 198-200 C. Smp.: 220,7 (DSC) (sønderdeling ved smeltning)Mp. : 198-200 C. Mp: 220.7 (DSC) (decomposition by melting)
Claims (4)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| GB8827391 | 1988-11-23 |
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| DK586789D0 DK586789D0 (en) | 1989-11-22 |
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| DK174543B1 true DK174543B1 (en) | 2003-05-19 |
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| DK198905867A DK174543B1 (en) | 1988-11-23 | 1989-11-22 | Process for the preparation of 2- [2- [4 - [[((4-chlorophenyl) phenylmethyl)] - 1-piperazinyl] ethoxy] acetic acid and its dihydrochloride and starting compound for use in the process |
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| KR (1) | KR970009728B1 (en) |
| AT (1) | AT398971B (en) |
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| 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) |
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| AU703690B2 (en) * | 1992-09-24 | 1999-04-01 | Sepracor, Inc. | Methods for treating allergic disorders using optically pure (+)cetirizine |
| GB9305282D0 (en) * | 1993-03-15 | 1993-05-05 | Ucb Sa | Enantiomers of 1-(4-chlorophenyl)phenylmethyl)-4-(4-methylphenyl)sulphonyl)piperazine |
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| 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 |
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| TR201009398A2 (en) | 2010-11-11 | 2012-05-21 | Bi̇lgi̇ç Mahmut | Tablet formulations with improved physical properties |
| WO2012101475A1 (en) | 2011-01-27 | 2012-08-02 | Jubilant Life Sciences Limited | An improved process for the preparation of antihistaminic drugs via a novel carbamate intermediate |
| CN103044355A (en) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | Key intermediate for synthesizing levocetirizine and preparation method thereof |
| 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 |
| CN104045607B (en) * | 2014-05-21 | 2016-04-13 | 丽珠医药集团股份有限公司 | A kind of purification process of cetrizine hcl |
| CN105924409B (en) * | 2016-05-12 | 2019-01-08 | 浙江永宁药业股份有限公司 | The method for splitting of one kind (R) -1- ((2- chlorphenyl)-(phenyl)-methyl)-piperazine |
| CN111205247B (en) * | 2020-04-22 | 2020-08-14 | 湖南九典宏阳制药有限公司 | Preparation method of levocetirizine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO155805C (en) * | 1981-02-06 | 1987-06-10 | Ucb Sa | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 2- (4- (DIPHENYLMETHYL) -1-PIPERAZINYL) -ACDIC ACIDS AND THEIR AMIDS AND NON-TOXIC 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 ES ES8903975A patent/ES2021907A6/en not_active Expired - Lifetime
- 1989-11-22 PL PL1989282410A patent/PL161379B1/en unknown
- 1989-11-22 NO NO894651A patent/NO172342C/en not_active IP Right Cessation
- 1989-11-22 AT AT0266589A patent/AT398971B/en not_active IP Right Cessation
- 1989-11-22 HU HU896131A patent/HU205094B/en not_active IP Right Cessation
- 1989-11-22 FI FI895564A patent/FI91862C/en not_active IP Right Cessation
- 1989-11-22 DK DK198905867A patent/DK174543B1/en not_active IP Right Cessation
- 1989-11-23 PH PH39570A patent/PH25982A/en unknown
- 1989-11-23 KR KR1019890017040A patent/KR970009728B1/en not_active IP Right Cessation
-
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
-
1993
- 1993-05-14 CY CY1671A patent/CY1671A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT92364A (en) | 1990-05-31 |
| GR1000553B (en) | 1992-08-26 |
| GB8827391D0 (en) | 1988-12-29 |
| HU896131D0 (en) | 1990-02-28 |
| HUT53627A (en) | 1990-11-28 |
| DK586789A (en) | 1990-05-24 |
| PH25982A (en) | 1992-01-13 |
| NO894651D0 (en) | 1989-11-22 |
| PT92364B (en) | 1995-07-18 |
| PL161379B1 (en) | 1993-06-30 |
| FI91862B (en) | 1994-05-13 |
| CY1671A (en) | 1993-05-14 |
| FI91862C (en) | 1994-08-25 |
| ATA266589A (en) | 1994-07-15 |
| KR900007825A (en) | 1990-06-02 |
| NO172342B (en) | 1993-03-29 |
| AT398971B (en) | 1995-02-27 |
| FI895564A0 (en) | 1989-11-22 |
| HK95892A (en) | 1992-12-11 |
| ES2021907A6 (en) | 1991-11-16 |
| CA1317300C (en) | 1993-05-04 |
| GR890100770A (en) | 1990-12-31 |
| NO894651L (en) | 1990-05-25 |
| GB8926243D0 (en) | 1990-01-10 |
| NO172342C (en) | 1993-07-07 |
| DK586789D0 (en) | 1989-11-22 |
| SG89492G (en) | 1992-12-04 |
| GB2225321B (en) | 1992-04-08 |
| KR970009728B1 (en) | 1997-06-17 |
| HU205094B (en) | 1992-03-30 |
| GB2225321A (en) | 1990-05-30 |
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