PH25982A - A process for the preparation of 2-(2-((4-chlorophenyl) phenyl-methyl)-1-piperazinyl) ethoxy) acetic acid and its dihydrochloride - Google Patents
A process for the preparation of 2-(2-((4-chlorophenyl) phenyl-methyl)-1-piperazinyl) ethoxy) acetic acid and its dihydrochloride Download PDFInfo
- Publication number
- PH25982A PH25982A PH39570A PH39570A PH25982A PH 25982 A PH25982 A PH 25982A PH 39570 A PH39570 A PH 39570A PH 39570 A PH39570 A PH 39570A PH 25982 A PH25982 A PH 25982A
- Authority
- PH
- Philippines
- Prior art keywords
- chlorophenyl
- phenylmethyl
- formula
- piperazinyl
- dihydrochloride
- Prior art date
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims description 18
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 7
- -1 2-(2-((4-chlorophenyl) phenyl-methyl)-1-piperazinyl) ethoxy Chemical group 0.000 title description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 29
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 21
- 239000011541 reaction mixture Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 2
- WPYUCWSMVJJWFI-UHFFFAOYSA-N 2-ethoxyacetonitrile Chemical compound CCOCC#N WPYUCWSMVJJWFI-UHFFFAOYSA-N 0.000 claims 1
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 claims 1
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 claims 1
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 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 description 9
- 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 150000002825 nitriles Chemical class 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
- 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
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960001803 cetirizine Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 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
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 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 description 2
- 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 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 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 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
- 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- RDFIZBYHUOHTQI-UHFFFAOYSA-N methyl 2-(2-chloroethoxy)acetate Chemical compound COC(=O)COCCCl RDFIZBYHUOHTQI-UHFFFAOYSA-N 0.000 description 1
- BYCHNMFDSQCCDD-UHFFFAOYSA-N methyl 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetate Chemical compound C1CN(CCOCC(=O)OC)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 BYCHNMFDSQCCDD-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium 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
- 239000000126 substance Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
Description
h B pe F157 voc 25982
A process for the preparation of 2-{2-{4-[(4-chlorophenyl)phenylmethyl}- l-piperazinyl Jethoxy]-acetic acid and its dihydrochloride.
The present invention relates to a new process for ‘the preparation of 2-{2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]e hogy-acetic acid 2 of the formula : o at = 8B i: i- 2 = az
AR 5 Ei
CH-N N-(CH.),-0-CH_.CCOH (1) EE / _/ = oc “ S nr 7 \ in wich the asterisk indicates the centre of asymmetry of the molecule, and its dihydrochloride.
The compound of the formula I may exist in the levorotatory form, the dextrorotatory form or a mixture of the levorotatory and dextrorotatory forms.
The present invention relates to the synthesis of the compound of the formula I in these various forms,
The dihydrochloride of 2-{2-(4-{(4-chlorophenyl)phenylmethyl]-1- piperazinyl Jethoxy]-acetic acid, also known by the generic name of cetirizine, has recently been introduced as a new medicament for the treatment of allergic syndromes, such as chronie and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria etc..
European Patent No.58,146 in the name of the Applicant describes the synthesis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1- piperazinyl Jethoxy-acetic acid and its dihydrochloride. In this synthesis, the starting substance is 1-[(4-chlbrophenyl)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 27.82. 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 easily converted into the free acid, and then into cetirizine dihydrochloride. , ( 'b 1 an "BAD ORIGINAL .
LI . 95982 e Ft
The major disadvantage of this synthesis is that the overall yield of 2-[2-[4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride is only 10.6Z, based on the amount of 1-[(4- chlorophenyl)-phenylmethyl]-piperazine employed.
According to the present invention, a new process for the synthesis is provided, which enables 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1- piperazinyl ]ethoxy]-acetic acid and its dihydrochloride to be prepared with better yields.
According to the present invention, 2-{2-[4-[(4- chlorophenyl)phenylmethyl]-1-piperazinylJethoxy]-acetic acid of the formula
So N-(CH,),-0-CH,-COOH (I) and its dihydrochloride are prepared by a process which is characterized in that 2-{2-(4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]- acetonitrile of the formula ad
A \ \ / \
CH-N N-(CH,_),-0-CH_-CN (IT) / s / 2°2 2 is hydrolysed in an aqueous, alcoholic or aqueous-alcoholic medium by a base or by an acid, and in that, if desired, the acid of the formula I thus obtained is converted into its dihydrochloride. : . 2-[2-(4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyljethoxy]- : acetonitrile of the formula II used as the starting material is a new compound which is easily obtained by reacting 1-[(4- cee hd UA 2 oo BAD ORIGINAL oo - 25982 chlorophenyl)phenylmethyl |-piperazine of the formula III with 2- haloethoxyacetonitrile of the formula IV in accordance with the equation: “AN rr me X-(cq,),-0-CH,-CN / Nn —————— = (IV) — (IZ /=\
TNA n
VN
CHE-H N-(CH.),-9-C&_ -2u jE — \ (ZZ) in which X represents a halogen atom.
This reaction is carried out in the presence of an acid acceptor, such as 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 (for example n-butanol etc.), preferably at a temperature close to the reflux ‘temperature.
When an optically active 1-((4-chlorophenyl)phenylmethyl]-piperazine of the formula III instead of the racemate is used in this reaction, the starting enantiomer can be obtained by resolution of the corresponding racemic compound by methods which are known per se. " Of the optically active acids which can be used for this resolution, tartaric acid is preferably used.
As regards the 2-haloethoxyacetonitriles of the formula IV, and more particularly 2-chloroethoxyacetonitrile, these products can be prepared in accordance with the method described by E.J. SALMI et al., Suomen
Kemistilehti, 17B,(1944),17-19 (Chem. Abstr. 40,(1946),6491).
The 2-(2-(4-((4-chlorophenyl)phenylmethyl]-1-piperazinyljethoxy]- 3 vo
BAD ORIGINAL
Cem mea memati acetic acid of the formula I is obtained by hydrolysis of 2-[2-[4-{(4- chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]-acetonitrile of the formula II in accordance with the equation: “ON choi top —_— (1)
Q N
— (IT)
This hydrolysis can be carried out by two operating methods, one in a basic medium and the other in an acid medium. 1. Hydrolysis of the nitrile in a basic medium
The nitrile of the 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.
The acid of the formula I formed is present in the reaction mixture in the form of its alkali metal salt, from which the acid is liberated by acidification of the reaction mixture by means of an inorganic acid (such as hydrochloric acid). The acid of the formula I is then extracted by means of an organic solvent (dichloromethane, toluene etc.) and crystallized for isolation.
Finally, the acid of the formula I is converted into the dihydrochloride by a process which is known per se. 2. Hydrolysis of the nitrile in an acid medium
The nitrile of the 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 acid of the formula I formed is then extracted from the reaction mixture by means of an organic solvent (dichloromethane, toluene etc.) and purified by crystallization.
The free acid of the formula I is then converted into the dihydrochloride by a process which is known per se.
This new synthesis process gives yields of cetirizine dihydrochloride,
calculated with respect to the amdunt of 1-[(4- chlorophenyl)phenylmethyl]-piperazine employed, 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 process. These higher yields starting from 1-(4- chlorophenyl)phenylmethyl]-piperazine constitute a considerable technical advance with respect to the process described in European
Patent No.58,146.
The following examples are given for the purpose of illustrating the invention.
Example 1. Preparation of racemic 2-[2-[4[(4-chlorophenyl)- phenylmethyl]-1-piperazinyl Jethoxy]-acetic dihydrochloride of the formule I. 1. Racemic 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyljethoxy]- acetonitrile of the formula II. 200 ml of n-butanol, 43.05 g (0.15 mole) of racemic 1-[(4- chlorophenyl)phenylmethyl]-piperazine, 24 g (0.174 mole) of 2- chloroethoxyacetonitrile, 26.1 g (0.246 mole) of sodium carbonate and 0.78 g (0.0047 mole) of potassium iodide are introduced successively 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 11 hours while stirring, cooled, filtered and concentrated on a rotary evaporator. 60 g of a yellow-brown oil are isolated and are chromatographed over a column containing 1 kg of silica using a mixture containing, by volume, 98% dichloromethane and 22 methanol.
This desired nitrile is collected in two fractions, from which the solvents are removed and the purity of which is measured by high performance liquid chromatography.
Racemic 2-([2-([4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]- 30 . acetonitrile is thus obtained in two fractions, one of which of 33.6 g has a purity of 100 and the other of which of 14.4 g has a purity of 97.4%.
Yield: 86.42
The product obtained can be characterized in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrochloric acid.
M.P.: 201-202°C.
Analysis for C, H_ CIN 0.2HCl in Z ' 21°24 3 } tot. calc.: C 56.96 H 5.91 N 9.48 Cl 16.01 Cl 24.02 found: C 57.21 H 6.00 N 9.49 cl” 15.78 c1®°%" 23.76
S 2. Racemic 2-{2-J4- (4-chlorophenyl)phenylmethyl}-1-piperazinyl]ethoxy]- acetic acid of the formula I (by hydrolysis in a basic medium) 250 ml of ethanol, 23 g (0.062 mole) of racemic 2-[2-{4-[(4- chlorophenyl)phenylmethyl]-1-piperazinyljethoxy]-acetonitrile and 31 ml of a 4N ethanolic solution of potassium hydroxide are introduced successively into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The reaction mixture is refluxed for 10 hours, while stirring. The reaction mixture is allowed to cool and its pH is brought to 6 by addition of 371 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 concentrated in a rotary evaporator. An oil is obtained and is allowed to crystallize by addition of 100 ml of 2-butanone, while hot. The solid formed is filtered, washed and dried. 18.9 g of racemic 2-(2-[4-((4- chlorophenyl)phenylmethyl]-1-piperazinyl}ethoxy]-acetic acid are thus obtained. 18.9 g of the acid thus obtained are resuspended in 150 ml of water; the pH is brought to 0.8 by addition of concentrated hydrochloric acid. The aqueous solution is concentrated on a rotary evaporator and the residue is then diluted by addition of 75 ml of 2-butanone and concentrated again. The addition of 150 ml of 2-butanone to the residue thus obtained causes crystallization of racemic 2-[2-[4-[(4- chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride. The crystals are filtered off and dried, 21.7 g being ~ obtained.
Yield: 75.927. M.P.:220.15°C (Differential Scanning Calorimetry; DSC) (decomposition on melting)
Analysis for C, H,sCLN,0,.2HCL in * Lo
Calc.: C 54.56 H 5.84 N 6.06 Cl 15.37 cl ' 23.05 found: C 54.60 H 5.86 N 6.02 Cl™ 15.33 c1tot 23.26
The overall yield of dihydrochloride of the 2-[2-(4-{(4- chlorophenyl)phenylmethyl}-1-piperazinyl]ethoxy]-acetic acid,
oo 25982
SN calculated with respect to the amount of l-{(4-chlorophenyl)- phenylmethyl )-piperazine employed, is 65.6%. 3. Racemic 2-[2-[4-f(4-chlorophenyl)phenylmethyl}-l-piperazinyl]ethoxy]- acetic acid of the formula I (by hydrolysis in an acid medium) 45.3 g (0.123 mole) of racemic 2-[2-[4-[(4-chlorophenyl)phenylmethyl]- l-piperazinyl Jethoxy]}-acetonitrile are introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and are heated to 45°C, while stirring. 41 ml of 372% concentrated hydrochloric acid are then introduced dropwise. The temperature of the reaction mixture rises to 92°C; the reaction mixture is heated at 95°C for 90 minutes, while stirring. The reaction mixture is allowed to cool and is concentrated on a rotary evaporator, the residue is taken up in 150 ml of toluene and the reaction mixture is concentrated again on a rotary evaporator. The residue is dissolved in 200 ml of water and the aqueous solution obtained is brought to pH
S by addition of sodium hydroxide. The solution is extracted three times with 300 ml of dichloromethane. The organic phases are combined and the solvent is removed on a rotary evaporator. The oil thus obtained is allowed to crystallize by being dispersed in 250 ml of 2- butanone, while hot.
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 thus isolated. 34 g of the acid thus obtained are resuspended in 300 ml of water; the pH is brought to 0.8 by addition of concentrated hydrochloric acid.
The aqueous solution is concentrated on a rotary evaporator, the residue is then diluted by addition of 150 ml of 2-butanone and the mixture is concentrated again. The addition of 300 ml of 2-butanone to the residue thus obtained causes crystallization of racemic 2-[2-(4- [(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride. The crystals are filtered off and dried, 39.7 g being obtained.
Yield: 70%. M.P.: 227.02°C (DSC) (decomposition on melting).
Analysis for C,,H,sC1N,0,.2HC1 in r Cor
Calc.: C 54.56 h 5.84 N 6.06 Cl 15.37 Cl ' 23.05 found: C 54.30 H 5.88 N 6.83 cl™ 15.56 c1°°%" 23.06
The overall yield of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]}-1- piperazinyl jethoxy]-acetic acid dihydrochloride, calculated with 7 a oo "25982 — respect to the amount of 1-[4-chlorophényl)phenylmethyl]-piperazine employed, is 60.52.
Example 2. Preparation of dextrorotatory 2-[2-[4-[(4- chlorophenyl)phenylmethyl}-1-piperazinyljethoxy]-acetic acid dihydrochloride of the formula I. 1. Levorotatory 1-[(4-chlorophenyl)phenylmethyl]-piperazine of the formula ITI.
A solution of 300 g (2 moles) of (2R,3R)-tartaric acid in 2 litres of ethanol is heated at 72-74°C and a solution of 286.5 (1 mole) of racemic 1-{(4-chlorophenyl)phenylmethyl)-piperazine in 1 litre of ethanol is added, while stirring. The mixture is.refluxed for 5 minutes and then allowed to return to room temperature, while stirring (the desired salt starts to crystallize towards 57°C). The salt obtained is filtered off and recrystallized three times in succession, first in a mixture of 2 litres of ethanol and 0.8 litre of methanol, then in 1 litre of ethanol, and finally in a mixture of 0.5 litre of ethanol, 65 ml of methanol and 5 ml of water. After filtration and drying, 118 g of diastereoisomerically impure 1-[4- chlorophenyl)phenylmethyl]-piperazine (2R,3R)-tartrate are obtained.
M.P.: 170.4°C (DSC). [@)2 : + 7.8° (c = 1, methanol).
This salt is then decomposed by addition of a solution of 22 g (0.55 mole) of sodium hydroxide in 750 ml of water. Levorotatory 1-[(4- chlorophenyl)phenylmethyl ]-piperazine thus liberated is extracted several times with dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and concentrated on a rotary evaporator. 80 g of optically impure levorotatory 1-[(4- chlorophenyl)phenylmethyl]-piperazine are obtained; this product is purified by successive recrystallizations from hexane, to give finally 18.2 g of levorotatory 1-[(4-chlorophenyl)phenylmethyl]-piperazine.
M.P.: 90-92°C,. M.P.: 90.35°C (DSC) (2)? : -19,4° (c = 1, toluene).
Yield: 12.7Z 2. Levorotatory 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]- ethoxy]-acetonitrile of the formula II. 100 ml of n-butanol, 20 g (0.07 mole) of levorotatory 1-[(4- chlorophenyl)phenylmethyl)-piperazine, 11.2 g (0.0937 mole) of 2- chloroethoxyacetonitrile, 12.18 g (0.115 mole) of sodium carbonate
[LQ 0 6 _ 209 OG and 0.36 g (0.002 mole) of potassium’ iodide are introduced successively 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 7 hours, while stirring, then cooled, filtered and concentrated on a rotary evaporator. 26 g of a yellow-brown oil are isolated and are chromatographed over a column containing 1 kg of silica using a mixture containing by volume, 98% dichloromethane and 2% methanol. 17.8 g of levorotatory 2-{2-[4-[(4-chlorophenyl)- phenylmethyl ]-1-piperazinyl ]Jethoxy]-acetonitrile are obtained in the form of an oil. (@)5as -31,8° (c = 1, methanol). Yield: 69X.
The product can be characterized in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrochloric acid.
M.P.: 211-212°C (2): +7.18° (c = 1, methanol)
Analysis for C,,H,,C1N,0.2HC] in 2 ] coe
Calc.: C 56.96 H 5.91 N 9.49 Cl 16.01 Cl "24.02 found: C 56.92 H 5.93 N 9.33 cl” 15.76 c1™°%" 23.65 3. Dextrorotatory 2-[2-[4-[(4-chlorophenyl-phenylmethyl]-1-piperazinyli}- ethoxy)-acetic acid dihydrochloride of the formula I. 9.42 g (0.0255 mole) of levorotatory 2-([2-[4-[(4- chlorophenyl)phenylmethyl]-1-piperazinyl Jethoxy)-acetonitrile are introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and are heated to 45°C, while stirring. 15 ml of 37% concentrated hydrochloric acid are then added. The temperature of the reaction mixture rises to 92°C. The reaction mixture is heated at 60°C for 60 minutes, while stirring. The reaction mixture is allowed to cool and is concentrated on a rotary evaporator, and the residue is taken up in 50 ml of water. The pH of the reaction mixture is brought to 5 by addition of sodium hydroxide and the mixture is extracted with several successive fractions of dichloromethane. The organic phases are combined and dried over magnesium sulphate and the solvent is removed on a rotary evaporator. 9.6 g of the free acid of the formula I are thus obtained in the form of a beige powder and are converted into the dihydrochloride by means of a solution of hydrochloric acid in acetone, and the dihydrochloride is crystallized. After filtration and drying, 9.8 g of dextrorotatory 2-[2-[4-[(4-chlorophenyl)phenylmethyl]}-1- 9 . . i
[I ' . "25982 piperazinyl]ethoxy]-acetic acid dihydtochloride are obtained. The purity of this product, measured by high performance liquid chromatography with a chiral stationary phase of «, -AGP (from the LKB
Company) is 95% with respect to the dextrorotatory enantiomer.
M.P.: 199-201°C M.P.:224.4°C (DSC). (12, : 49.4° (c = 1, water)
Yield: 832
Analysis for C, H,5C1N,0,.2HCL in tr tot calc.: C 54.56 H 5.84 N 6.06 Cl 15.37 Cl © 23.05 found: C 54.00 H 5.88 N 5.91 cl” 15.55 c1®°%" 23.13
The overall yield of dextrorotatory 2-[2-[4-[(4- chlorophenyl)phenylmethyl}-1-piperazinyl]ethoxy]-acetic acid dihydrochloride, calculated with respect to the amount of levorotatory 1-[4-chlorophenyl-phenylmethyl]-piperazine employed, is 57.3%.
Example 3. Preparation of levorotatory 2-[2-[4-J (4- chlorophenyl)phenylmethyl]-1-piperazinyl Jethoxyj-acetic acid dihydrochloride of the formula I.
This product is obtained by the method described in example 2, but starting from dextrorotatory 1-[ (4-chlorophenyl)phenylmethyl]-piperazine, the latter being obtained as in example 2.1 by treating the racemate with (25,3S)-tartaric acid.
The levorotatory acid dihydrochloride of the formula I is obtained in yields and with a purity very close to those obtained for the dextrorotatory acid dihydrochloride: 95 measured by high performance liquid chromatography with a chiral stationary phase of a, -AGP (from the
LKB Company). .
M.P.: 198-200°C M.P.: 220.7 (DSC) (decomposition on melting).
Claims (4)
1. In a process for the preparation of 2-[2-[4- ’ {(4-chlorophenyl)phenylmethyll-l-piperazinyllethoxyl]- acetic acid of the formula LA 1 n-(eay);-0-cry-coon (1) and its dihydrochloride, wherein a 2-02-14-1(4- chlorophenyl)phenylmethyl]-1-piperazinyllethoxyl- acetic acid derivative is hydrolysed at a temperature between 60 C and the reflux temperature of the reaction mixture, in an aqueous, alcoholic or aqueous- : alcoholic medium by a base or by an acid, and wherein, if desired, the acid thus obtained is converted into its dihydrochloride, the improvement which comprises using 2-{2-{4-[(4-chlorophenyl)phenylmethyl]-1-pipe- razinyllethoxyl-acetonitrile of the formula “0 cur (CHz),-0-CH,- CN (I1) as starting material for the hydrolysis.
2. A process according to claim 1, wherein the 2- {2-14-((4-chlorophenyl)phenylmethyl]-1-piperazinyl] ethoxyl-acetic acid of the formula I is in the levorotatory or dextrorotatory form or in the form of a mixture of the 1levorotatory and dextrorotatory forms.
3. A process according to claims 1, wherein the 2-2-{4-l(4-chlorophenyl)phenylmethyl]-1-piperazinyl]l ethoxyl-acetonitrile of the formula II is in the levorotatory or dextrorotatory form or in the form of ta . a mixture of the dextrorotatory and levorotatory bY forms.
4. 2-[2-4-[(4-chlorophenyl)phenylmethyll-1-pipe- \ razinyllethoxyl-acetonitrile of the formula “CA CH-N -(CH_).-0O-CH_-CN / NA 2)2 2 (11) and its dihyrochloride in the levorotatory or dextrorotatory form or in the form of a mixture of the levorotatory and dextrorotatory forms.
Applications Claiming Priority (1)
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH25982A true PH25982A (en) | 1992-01-13 |
Family
ID=10647347
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH39570A PH25982A (en) | 1988-11-23 | 1989-11-23 | A process for the preparation of 2-(2-((4-chlorophenyl) phenyl-methyl)-1-piperazinyl) ethoxy) acetic acid and its dihydrochloride |
Country Status (16)
| Country | Link |
|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH08501562A (en) * | 1992-09-24 | 1996-02-20 | セプラコア，インコーポレイテッド | METHODS AND COMPOSITIONS FOR TREATMENT OF ALLERGIC DISEASES USING OPTICALLY PURE (+) CETIRIDINE |
| CA2145410A1 (en) * | 1992-09-24 | 1994-03-31 | Nancy M. Gray | Compositions for treating allergic disorders using (-) cetirizine |
| 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 |
| 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. |
| WO1998055459A1 (en) | 1997-06-04 | 1998-12-10 | Azwell Inc. | 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 |
| US6977301B1 (en) | 2001-05-29 | 2005-12-20 | Ucb, S.A. | Process for preparing (S) and (R)—2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide |
| US7199241B1 (en) | 2001-05-29 | 2007-04-03 | Ucb, S.A. | Process for preparing (S) and (R)-2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide |
| AU2004205494B2 (en) * | 2003-01-23 | 2009-04-30 | Ucb Farchim Sa | Piperazine derivatives and their use as synthesis intermediates |
| KR100503443B1 (en) | 2004-02-02 | 2005-07-22 | 한림제약(주) | Processes for preparing an optically active cetirizine or its salt |
| NZ556580A (en) * | 2005-03-03 | 2009-08-28 | Ucb Farchim Sa | Pyroglutamate salts and their use in the optical resolution of intermediates for the synthesis of dextrocetirizine and levocetirizine |
| HU227325B1 (en) * | 2005-12-08 | 2011-03-28 | Egis Gyogyszergyar Nyrt | Process for the production of an intermediate of (dextro- and levo)- cetirizine |
| WO2008110586A2 (en) | 2007-03-12 | 2008-09-18 | Krka, Tovarna Zdravil, D.D., Novo Mesto | New process for the preparation of levocetirizine and intermediates thereof |
| SI22489A (en) * | 2007-03-12 | 2008-10-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | New procedure for preparation of levocetirizine and its intermediates |
| US8084606B2 (en) | 2007-06-15 | 2011-12-27 | Symed Labs Limited | Process for preparation of substantially optically pure levorotatory and dextrorotatory enantiomers of cetirizine using novel intermediates |
| WO2009062036A2 (en) * | 2007-11-09 | 2009-05-14 | Dr. Reddy's Laboratories Ltd. | Processes for preparing levocetirizine and pharmaceutically acceptable salts thereof |
| PL2062881T3 (en) | 2007-11-21 | 2011-07-29 | Synthon Bv | Process for making N-(diphenylmethyl)piperazines |
| US7989623B2 (en) | 2007-11-21 | 2011-08-02 | Synthon Bv | Process for making n-(diphenylmethyl)piperazines |
| AU2009254959B2 (en) | 2008-06-02 | 2014-01-30 | Cipla Limited | Processes for the synthesis of levocetirizine and intermediates for use therein |
| EP2297122B1 (en) * | 2008-06-11 | 2014-05-21 | KRKA, tovarna zdravil, d.d., Novo mesto | New process for the preparation of levocetirizine and intermediates thereof |
| KR100998067B1 (en) | 2008-09-08 | 2010-12-03 | 주식회사 삼오제약 | A novel Bis1-[4-chlorophenylphenylmethyl]piperazine-2,3-Dibenzoyl tartarate intermediate salt and the method for isolating optically active 1-[4-chlorophenylphenylmethyl]piperazine using thereby |
| WO2010046908A2 (en) | 2008-09-17 | 2010-04-29 | Calyx Chemicals And Pharmaceuticals Pvt. Ltd. | Novel water based process for the preparation of substituted diphenylmethyl piperazines |
| WO2010107404A1 (en) | 2009-03-16 | 2010-09-23 | Mahmut Bilgic | Stable pharmaceutical combinations |
| TR201007652A2 (en) | 2010-09-20 | 2012-04-24 | Bi̇lgi̇ç Mahmut | Synergistic effect. |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 PL PL1989282410A patent/PL161379B1/en unknown
- 1989-11-22 ES ES8903975A patent/ES2021907A6/en not_active Expired - Lifetime
- 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 NO NO894651A patent/NO172342C/en not_active IP Right Cessation
- 1989-11-22 DK DK198905867A patent/DK174543B1/en not_active IP Right Cessation
- 1989-11-22 AT AT0266589A patent/AT398971B/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
-
1993
- 1993-05-14 CY CY1671A patent/CY1671A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CY1671A (en) | 1993-05-14 |
| ES2021907A6 (en) | 1991-11-16 |
| GB8827391D0 (en) | 1988-12-29 |
| GR1000553B (en) | 1992-08-26 |
| NO894651L (en) | 1990-05-25 |
| GR890100770A (en) | 1990-12-31 |
| SG89492G (en) | 1992-12-04 |
| PT92364A (en) | 1990-05-31 |
| DK586789D0 (en) | 1989-11-22 |
| PT92364B (en) | 1995-07-18 |
| DK586789A (en) | 1990-05-24 |
| KR970009728B1 (en) | 1997-06-17 |
| NO894651D0 (en) | 1989-11-22 |
| HUT53627A (en) | 1990-11-28 |
| NO172342C (en) | 1993-07-07 |
| DK174543B1 (en) | 2003-05-19 |
| AT398971B (en) | 1995-02-27 |
| GB8926243D0 (en) | 1990-01-10 |
| HU205094B (en) | 1992-03-30 |
| GB2225321B (en) | 1992-04-08 |
| CA1317300C (en) | 1993-05-04 |
| NO172342B (en) | 1993-03-29 |
| FI895564A0 (en) | 1989-11-22 |
| PL161379B1 (en) | 1993-06-30 |
| HU896131D0 (en) | 1990-02-28 |
| FI91862B (en) | 1994-05-13 |
| FI91862C (en) | 1994-08-25 |
| ATA266589A (en) | 1994-07-15 |
| KR900007825A (en) | 1990-06-02 |
| GB2225321A (en) | 1990-05-30 |
| HK95892A (en) | 1992-12-11 |
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