PH26334A - A process for the preparation of 2-[2-[4-[(4 chloro phenyl) phenyl methyl]-1-piperazinyl]ethoxy]-acetic and its dihydrochloride - Google Patents
A process for the preparation of 2-[2-[4-[(4 chloro phenyl) phenyl methyl]-1-piperazinyl]ethoxy]-acetic and its dihydrochloride Download PDFInfo
- Publication number
- PH26334A PH26334A PH39569A PH39569A PH26334A PH 26334 A PH26334 A PH 26334A PH 39569 A PH39569 A PH 39569A PH 39569 A PH39569 A PH 39569A PH 26334 A PH26334 A PH 26334A
- Authority
- PH
- Philippines
- Prior art keywords
- chlorophenyl
- phenylmethyl
- piperazinyl
- dihydrochloride
- ethoxy
- Prior art date
Links
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims description 29
- 238000000034 method Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 title description 23
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 title description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims description 9
- 150000001340 alkali metals Chemical class 0.000 claims description 8
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 7
- 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 description 6
- -1 alkali metal salt Chemical class 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 239000012429 reaction media Substances 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 230000003247 decreasing effect Effects 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229960000443 hydrochloric acid Drugs 0.000 description 5
- 235000011167 hydrochloric acid Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZJQSBXXYLQGZBR-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethanol Chemical compound C1CN(CCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZJQSBXXYLQGZBR-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229960001803 cetirizine Drugs 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229940089960 chloroacetate Drugs 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 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 1
- ALKWTKGPKKAZMN-UHFFFAOYSA-N 1-chloro-4-[chloro(phenyl)methyl]benzene Chemical compound C=1C=C(Cl)C=CC=1C(Cl)C1=CC=CC=C1 ALKWTKGPKKAZMN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
. Ci . SL ,
Lo - ® ° O) . 5
A process for the preparation of 2-{2-f{4-[(4-chlorophenyl)phenylmethyl]- 1-piperazinyllethoxy)]-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]ethoxy]-acetic acid and its dihydrochloride.
The dihydrochloride of 2-(2-[4-[(4-chlorophenyl)phenylmethyl]}-1- piperazinyl]ethoxy]-acetic acid also known by the generit name of cetirizine, has recently been introduced as a new medicament for the treatment of allergic syndromes, such as chronic and acdte allergic rhinitis, allergic conjunctivitis, pruritus, urticaria ste. When dsed in therapy, this product has proved to be remarkably free-from side effects on the central nervous system, such as drowsiness, reduted mental, - performance etc.(c.f. D.P.TASHKIN et al., Annals of Allbrgy, Part II, 59, (1987),49-52, and F.M. GENGO et al., Annals of Allergy, Part II, 39, (1987),53-57). .
European Patent No.58,146 in the name of the Applicant describes the synthesis of 2-(2-[4-[(4-chlorophenyl)phenylmethyl]-1- } piperazinyl)ethoxy)-acetic acid and its dihydrochloride. In this synthesis, the starting substance is 1-[(4-chlorophenyl)phenylmethyl]- : cd piperazine, which is reacted with methyl (2-chloroethoxy)-acetate to give
CL methyl 2-[2-[4-[ (4-chlorophenyl)phenylmethyl]-1-piperazinyljethoxy]-
Co 20 acetate in a yield of 27.8%. This methyl ester is then subjected to
Sy hydrolysis with an inorganic base (potassium or sodium hydroxide) to give pi the sodium or potassium salt, which is easily converted into the free
Ee acid, and then into cetirizine dihydrochloride.
CE The major disadvantage of this synthesis is that the overall yield i 25 of 2-[2-(4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic
HE acid dihydrochloride is only 10.61%, based on the amount of 1l-{(&4-
A chlorophenyl)phenylmethyl ]-piperazine employed.
Si According to the present invention, a new process for the synthesis i is provided, which enables 2-[{2-[4-[(4-chlorophenyl)phenylmethyl}-1- piperazinyl Jethoxy]}-acetic acid and its dihydrochloride to be prepared g with better yields. ’
According to the present invention, 2-[2-[4-[(4- *
So chlorophenyl)phenylmethyl]-1-piperazinyl]-acetic acid and its — dihydrochloride are prepared by a process which is characterized in that
Fo 35 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl}-ethanol is reacted io with an alkali metal haloacetate in the presence of an alkali metal a 1
ST
BEE | , , . 2) ) alcoholate and in that the alkali metal salt thus obtained is converted : into the corresponding acid and, if appropriate, into its " dihydrochloride.
The 2-[{4-{(4-chlorophenyl)phenylmethyl-1-piperazinyl)-ethanol used as the starting substance in the process of the invention is a product which is known per se. Its synthesis by reaction of l-piperazineethanol with (4-chlorophenyl)phenylmethyl chloride has already been described in
U.S. Patent No.2,899,436. This product can also be prepared in a higher yield (90%) by reaction of 1-[(4-chlorophenyl)phenylmethyl]-piperazine : 10 with a 2-haloethanol in the presence of an acid acceptor, such as an inorganic base (for example sodium or potassium carbonate) or a tertiary organic base (for example triethylamine), in an inert solvent, such as toluene, xylene or another aromatic solvent.
In accordance with the invention, 2-{2-([4-[(4- chlorophenyl)phenylmethyl]}-1-piperazinyl]ethoxy]-acetic acid is obtained : by reaction of 2-[4-{(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol } and an alkali metal haloacetate, such as sodium chloroacetate. This reaction is generally carried out by heating at between 60 and 100°C for several hours in the presence of an alkali metal alcoholate, such as, for example, potassium tert-butoxide, and in an organic solvent, preferably : an aliphatic alcohol of low reactivity, such as, for example, tert- oy butanol.
Cl To achieve optimum yields, its is advisable to use potassium tert- gs butoxide and tert-butanol and to resupply the reaction medium regularly a 25 with the two reactants (alkali metal alcoholate and alkali metal . haloacetate) in smaller and smaller amounts and at regular intervals 3 : until the reaction is as complete as possible. no By way of example, each reactant can be added to the reaction so mixture every half hour for a total duration of four hours. Each of the
Le 30 total molar amounts of alcoholate and haloacetate used is advantageously oo 25 to 75% higher than the molar amount of the starting 2-[4-[(4- . | chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol.
For reasons of economy, it is of interest to recover and recycle ot the starting alcohol. To this effect, the solvent is removed from the
Fl 35 reaction medium, the latter is taken up in acidified water (to bring the * cL pH to a weakly basic value) and the starting alcohol is extracted with hg diethyl ether. The 2-[2-(4-[(4-chlorophenyl)phenylmethyl)-1- 2 piperazinyl)ethoxy]-acetic acid which is formed in the course of the
N CO \ i E ) 3 reaction is present in the reaction mixture in the form of an alkali : | metal salt. After the reaction mixture is acidified to pH 5 by addition : of an inorganic acid (such as hydrochloric acid), the corresponding acid can be recovered from the reaction mixture by extraction by means of an organic solvent (dichloromethane, toluene etc.). The desired acid can also be isolated in the form of well-crystallized salts. This acid can be converted into the corresponding dihydrochloride of the acid by a conventional process.
Co This new synthesis process gives yields of 44% or more of n 10 cetirizine dihydrochloride, calculated on the basis of the 1-[(4- . chlorophenyl)phenylmethyl]-1-piperazine employed. With recycling of the 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol in the reaction, the overall yield can even reach values close to 50X. This higher yield starting from 1-{ (4-chlorophenyl)phenylmethyl]-1-piperazine . 15 constitutes a considerable technical advance with respect to the process ol "described in European Patent No.58,146.
The following example is given for the purpose of illustrating the invention. i Example. Preparation of 2-[2-[(4-chlorophenyl)phenylmethyl]-1- - 20 piperazinyl]ethoxy]-acetic acid. 1. 2-[4-[4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol. 3 325 ml of dry toluene, 131.2 g (0.458 mole) of 1-[(4- +) chlorophenyl)phenylmethyl]-piperazine and 125 ml (0.9 mole) of or triethylamine are introduced successively into a three-necked round- a 25 bottomed flask of 2 litres capacity equipped with a mechanical .
Es stirrer, a condenser and a thermometer. 41.5 g (0.516 mole) of 2- a : chloroethanol are added to this solution and the mixture is brought nt to the reflux temperature, while stirring. After heating for six
A hours, a further 20 g (0.248 mole) of 2-chloroethanol are added and = 30 reflux is maintained for an additional six hours.
So The reaction mixture is cooled and filtered and the filtrate is
Wi concentrated under a vacuum on a rotary evaporator. 146.5 g of 2-[4- 1 { (4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol are thus
Ut isolated in the form of a yellow oil in a yield of 96.82. i 35 50 g of the alcohol obtained are distilled at 220°C under reduced *
Co pressure (0.0065 mbar) and collected in two separate fractions.
Ll The purity of each fraction is measured by high pressure liquid a chromatography. One fraction of 24.5 g has =a purity of 96.61, i 3
Sd
. oY t ’ 2) i whereas the other fraction (of 22.2 g) has a purity of 99.6%. A yield of pure product of 90.4% is thus obtained. : The alcohol thus obtained can be characterized in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrochloric acid.
M.P.: 222°C
Analysis for C, gH, 4CIN,0.2HCL in 2 calc : C 56.50 H 6.19 N 6.94 cl” 17.59 c1tot- 26.39 found: C 56.63 H 6.28 N 6.86 Cl 17.48 c1tot- 26.32 2. 2-[2-[4-](4-chlorophenyl)phenylmethyl]-l-piperazinyllethoxy]-acetic acid. 50 g (0.15 mole) of 2-[4-([(4-chlorophenyl)phenylmethyl]-1- piperazinyl]-ethanol and 225 ml of tert-butanol are introduced into a three-necked round bottomed flask equipped with a mechanical stirrer, a thermometer, a nitrogen inlet and a condenser. The mixture is stirred gently and heated to 45°C under a nitrogen ] atmosphere, and 21 g of potassium tert-butoxide are added. The temperature is raised to 75-80°C and the mixture is kept at this temperature. 11 g of sodium chloroacetate are then added to the mixture, taking the time of this addition as time zero. Sodium chloroacetate and potassium tert-butoxide are introduced successively into the reaction mixture, the temperature being kept y at 75-80°C and while stirring under a nitrogen atmosphere, in the a following manner: after 45 minutes 11 g of scdium chloroacetate are added; after 1 hour and a half 5.2 g of potassium tert-butoxide are
Lo added; after 2 hours 5.64 g of sodium chloroacetate are added;
Ea after 2 and a half hours 1.9 g of potassium tert-butoxide are added; after 3 hours 1.9 g of sodium chloroacetate are added; after 3 and ’ oo a half hours 0.8 g of potassium tert-butoxide is added; after 4
So 30 hours the operation is ended by addition of 1.13 g of scdium a chloroacetate. A total of 28.92 g (0.25 mole) of potassium tert- - butoxide (97%) and 30.65 g (0.25 mole) of sodium chloroacetate (951) has thus been added. The reactor is then converted into a distillation apparatus and about 150 ml of tert-butanol are - 35 distilled off; 190 ml of water are then added to the reaction . i mixture and the distillation of tert-butanol in the form of an
Ss azeotrope with water is continued until the temperature of the oo vapours reaches 100°C.
Ce a } . . } LL
The reaction mixture is cooled, diluted with 60 ml of water and brought to pH 8 by addition of about 8 ml concentrated hydrochloric - acid. The starting 2-[4-[ (4-chlorophenyl)phenylmethyl]-1- } piperazinyl)-ethanol which has not reacted is then carefully extracted with diethyl ether, which enables 7.3 g to be recovered after evaporation of the solvent.
The aqueous phase, which contains the sodium salt of the desired acid, is acidified to pH 5 by addition of hydrochloric acid and extracted three times with 200 ml of dichloromethane. The organic phases of the extraction are combined and dried over magnesium . sulphate, filtered and concentrated in a rotary evaporator. An oil is obtained and is allowed to crystallize by addition of 150 ml of 2-butanone, while hot. The solid formed is filtered off and dried. 32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-
CT 15 piperazinyl Jethoxy]-acid are thus isolated.
Yield: 55.52. M.P.:146-148°C. ) Analysis for C,H, CIN,0, in 1 calc.: C 64.86 H 6.48 N 7.20 cl 9.12 found: C 64.67 H 6.46 N 7.19 cl™ 9.39 - 20 A second crop of product can be obtained by concentration of the el mother liquors (7.4 g). . i 3. 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyljethoxy]-acetic
NE acid dihydrochloride. i 32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1- ol 25 piperazinyl)ethoxy]-acetic acid are suspended in a mixture of 125 ml
Ry of water and 13.8 ml of 37% aqueous hydrochloric acid. This mixture a is conceritrated on a rotary evaporator. An oil is obtained and is
SL crystallized by addition of 245 ml of 2-butanone. The crystals
Bh formed are filtered off, drained and dried. 34.2 g of 2-[2-[4-[(4-
LL 30 chlorophenyl)phenylmethyl]-1-piperazinyljethoxy]-acetic acid i dihydrochloride are obtained. 7 Yield: 887. M.P.: 228.22°C (Differential Scanning Calorimetry, DSC)
Analysis for C,,H,CIN,0,.2HC] in 2
LC J calc.: C 54.56 H 5.84 N 6.06 Cl 15.37 c1%°t 23.05 u 35 found: Css.28 H 5.86 N 6.15 cl 15.24 c1°% 23.22 : » ; A second crop of dihydrochloride can be obtained in the same way . starting from the second crop of product obtained above under point
Se 2 (4.5 g). oe 5 © i
CL 9) : « »
Taking into account the fact that the 2-[4-[(4- chlorophenyl)phenylmethyl}-1-piperazinyl]-ethanol is obtained in a yield of 90.4% from 1-[(4-chlorophenyl)phenylmethyl J-piperazine, the 2-[2-[4-((4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride is thus obtained in three steps in an overall yield of 44.12 (or more than 48% if possible recycling of 2-{4-[(4- chlorophenyl)phenylmethyl }-1-piperazinyl J-ethanol which has not reacted is taken into account), which constitutes a marked improvement with respect to the process according to European
Patent No. 58,146. i ' 6 i 1
Claims (1)
1. A process for the preparation of 2-[2-[4-[(4- : chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxyl-acetic acid and its dihydrochloride which comprises reacting, at a temperature between 60°C and 100°, 2-[4-1(4- chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol, ‘with sodium chloroacetate, in the presence of potassium tert- butoxide, and in tert-butanol, while resupplying the reaction medium regularly with the two reactants, the sodium chloroacetate and the potassium tert-butoxide, in decreasing amounts and at regular intervals, and ’ converting the sodium salt of 2-[2-[4-[(a- chlorophenyl)phenylmethyll-1-piperazinyllethoxyl-acetic acid thus obtained into the corresponding acid and into its dihydrochloride. Inventors: GUY BODSON ERIC COSSEMENT JEAN GOBERT
_ Cn a lL : ’ C } . . J 26334 ABSTRACT A process for the preparation of 2-{2-[4[(4-chlorophenyl)phenylmethyl]- l-piperazinyl]ethoxy)-acetic acid and its dihydrochloride, wherein 2- [4-[(4-chlorophenyl-phenylmethyl]-1-piperazinyl]-ethanol is reacted with an alkali metal halogenoacetate in the presence of an alkali metal alcoholate, the alkali metal salt thus obtained is converted into the : corresponding acid and, if appropriate, into its dihydrochloride. Co od A !
i. i 1
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888827390A GB8827390D0 (en) | 1988-11-23 | 1988-11-23 | Process for preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-pipera-zinyl)ethoxy)-acetic acid & its dihydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH26334A true PH26334A (en) | 1992-04-29 |
Family
ID=10647346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH39569A PH26334A (en) | 1988-11-23 | 1989-11-23 | A process for the preparation of 2-[2-[4-[(4 chloro phenyl) phenyl methyl]-1-piperazinyl]ethoxy]-acetic and its dihydrochloride |
Country Status (17)
| Country | Link |
|---|---|
| KR (1) | KR970009727B1 (en) |
| AT (1) | AT398970B (en) |
| CA (1) | CA1320732C (en) |
| CY (1) | CY1696A (en) |
| DK (1) | DK174289B1 (en) |
| ES (1) | ES2018967A6 (en) |
| FI (1) | FI91861C (en) |
| GB (2) | GB8827390D0 (en) |
| GR (1) | GR1000576B (en) |
| HK (1) | HK45493A (en) |
| HU (1) | HU208002B (en) |
| NO (1) | NO172287C (en) |
| PH (1) | PH26334A (en) |
| PL (1) | PL161374B1 (en) |
| PT (1) | PT92363B (en) |
| RU (1) | RU1838306C (en) |
| SG (1) | SG12793G (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0950412A3 (en) * | 1992-09-24 | 2001-05-16 | Sepracor, Inc. | Compositions for treating allergic disorders using (-) cetirizine |
| AU5136193A (en) * | 1992-09-24 | 1994-04-12 | Sepracor, Inc. | Methods and compositions for treating allergic disorders using optically pure (+) cetirizine |
| 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. |
| CA2180993A1 (en) * | 1996-07-11 | 1998-01-12 | Yong Tao | Methods for the manufacture of cetirizine |
| EP0919550A1 (en) | 1997-11-26 | 1999-06-02 | Ucb, S.A. | Pseudopolymorphic forms of 2-2-4-bis(4-fluorophenyl)methyl-1-piperazinyl-ethoxy acetic acid dihydrochloride |
| IL124195A (en) * | 1998-04-23 | 2000-08-31 | Chemagis Ltd | Process for the preparation of esters of 2-¬4-¬4-chlorophenyl¾phenylmethyl¾-1-piperazinyl¬ethoxy¾acetic acid |
| DK176706B1 (en) * | 1999-03-04 | 2009-03-30 | Sandoz As | Process for the preparation of 2- {2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy} -acetic acid compounds or salts thereof |
| US6265579B1 (en) * | 1999-10-29 | 2001-07-24 | Salsbury Chemicals, Inc. | Process for preparing piperazine-substituted aliphatic carboxylates |
| 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 |
| AU2003237394A1 (en) * | 2002-06-05 | 2003-12-22 | Dr. Reddy's Laboratories Limited | Crystalline (2-(4-((4-chlorophenyl)-phenyl methyl)-1-piperazinyl) ethoxy) acetic acid dihydrochloride |
| US7381821B2 (en) | 2003-01-23 | 2008-06-03 | Ucb, S.A. | Piperazine derivatives and their use as synthesis intermediates |
| WO2004103982A1 (en) * | 2003-05-21 | 2004-12-02 | Wockhardt Limited | 2-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]acetic acid monohydrochloride as anti-allergenic compound and process for its production |
| US20110172425A1 (en) | 2008-09-17 | 2011-07-14 | Calyx Chemicals And Pharmaceuticals Pvt. Ltd. | Novel water based process for the preparation of substituted diphenylmethyl piperazines |
| KR101418404B1 (en) | 2012-01-06 | 2014-07-10 | 한미약품 주식회사 | Stable pharmaceutical formulation for oral administration comprising levocetirizine or a pharmaceutically acceptable salt thereof, and montelukast or a pharmaceutically acceptable salt thereof |
| KR102226833B1 (en) | 2013-06-28 | 2021-03-12 | 한미약품 주식회사 | Complex granule formulation having improved stability comprising levocetirizine and montelukast |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB817231A (en) * | 1956-01-27 | 1959-07-29 | Henri Morren | New derivatives of n-mono-benzhydryl-piperazine and process for the preparation thereof |
| US3090725A (en) * | 1960-02-29 | 1963-05-21 | Burroughs Wellcome Co | Phosphorylated quaternary ammonium compounds of improved oral absorption |
| 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 GB888827390A patent/GB8827390D0/en active Pending
-
1989
- 1989-09-29 CA CA000614708A patent/CA1320732C/en not_active Expired - Fee Related
- 1989-11-20 GR GR890100771A patent/GR1000576B/en not_active IP Right Cessation
- 1989-11-21 GB GB8926242A patent/GB2225320B/en not_active Expired - Lifetime
- 1989-11-21 PT PT92363A patent/PT92363B/en not_active IP Right Cessation
- 1989-11-22 FI FI895563A patent/FI91861C/en not_active IP Right Cessation
- 1989-11-22 PL PL1989282411A patent/PL161374B1/en unknown
- 1989-11-22 RU SU894742406A patent/RU1838306C/en active
- 1989-11-22 DK DK198905865A patent/DK174289B1/en not_active IP Right Cessation
- 1989-11-22 AT AT0266489A patent/AT398970B/en not_active IP Right Cessation
- 1989-11-22 ES ES8903974A patent/ES2018967A6/en not_active Expired - Lifetime
- 1989-11-22 HU HU896130A patent/HU208002B/en not_active IP Right Cessation
- 1989-11-22 NO NO894650A patent/NO172287C/en not_active IP Right Cessation
- 1989-11-23 KR KR1019890017039A patent/KR970009727B1/en not_active IP Right Cessation
- 1989-11-23 PH PH39569A patent/PH26334A/en unknown
-
1993
- 1993-02-06 SG SG127/93A patent/SG12793G/en unknown
- 1993-05-13 HK HK454/93A patent/HK45493A/en not_active IP Right Cessation
-
1994
- 1994-01-14 CY CY160694A patent/CY1696A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK586589A (en) | 1990-05-24 |
| AT398970B (en) | 1995-02-27 |
| KR970009727B1 (en) | 1997-06-17 |
| PT92363B (en) | 1995-07-18 |
| HK45493A (en) | 1993-05-21 |
| HU208002B (en) | 1993-07-28 |
| GB2225320A (en) | 1990-05-30 |
| GB8827390D0 (en) | 1988-12-29 |
| FI91861C (en) | 1994-08-25 |
| PT92363A (en) | 1990-05-31 |
| KR900007824A (en) | 1990-06-02 |
| FI91861B (en) | 1994-05-13 |
| ES2018967A6 (en) | 1991-05-16 |
| GB2225320B (en) | 1992-09-02 |
| DK174289B1 (en) | 2002-11-18 |
| NO894650L (en) | 1990-05-25 |
| SG12793G (en) | 1993-04-16 |
| ATA266489A (en) | 1994-07-15 |
| NO172287C (en) | 1993-06-30 |
| GR1000576B (en) | 1992-08-26 |
| CA1320732C (en) | 1993-07-27 |
| PL161374B1 (en) | 1993-06-30 |
| HU896130D0 (en) | 1990-02-28 |
| GB8926242D0 (en) | 1990-01-10 |
| NO172287B (en) | 1993-03-22 |
| HUT53626A (en) | 1990-11-28 |
| DK586589D0 (en) | 1989-11-22 |
| NO894650D0 (en) | 1989-11-22 |
| FI895563A0 (en) | 1989-11-22 |
| CY1696A (en) | 1994-01-14 |
| GR890100771A (en) | 1990-12-31 |
| RU1838306C (en) | 1993-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| PH26334A (en) | A process for the preparation of 2-[2-[4-[(4 chloro phenyl) phenyl methyl]-1-piperazinyl]ethoxy]-acetic and its dihydrochloride | |
| CA1317300C (en) | Process for the preparation of 2-¬2-¬4-¬(4-chlorophenyl) phenylmethyl|-1-piperazinyl|ethoxy|-acetic acid and its dihydrochloride | |
| CN101454304A (en) | Process for the production of benzopyran-2-ol derivatives | |
| DK147421B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF PIPERAZINE DERIVATIVES OR ACID ADDITIONAL SALTS OR QUATERNARY AMMONIUM SALTS THEREOF | |
| US3337554A (en) | Piperazino and homopiperazino-10-11-dihydrobenzo[b, f]-thiepin | |
| US20090018337A1 (en) | Process for the preparation of a pharmaceutical intermediate | |
| JP6884857B2 (en) | Method for producing phenylalanine compounds | |
| CN110950818B (en) | Method for purifying cis-2, 6-dimethyl morpholine | |
| EP0295218B1 (en) | A process for the preparation of 2,4-diamino-6-(1-piperidinyl)-pyrimidine n-oxide | |
| US20130090475A1 (en) | Process for the Preparation of Ranolazine | |
| CA1041098A (en) | 1-(3-(naphthyl-1-yl-oxy)-propyl)-piperazine derivatives | |
| US3654271A (en) | Process for preparing simple and substituted morpholines | |
| US4225714A (en) | Process for preparing p-chlorophenoxy-acetyl-piperonylpiperazine hydrochloride | |
| FR2511246A1 (en) | NOVEL CYCLIC ALPHA-AMINODERIVATES OF 1- (3 ', 4'-METHYLENE-DIOXYPHENYL) ETHANOL AND PROCESS FOR PRODUCING THE SAME | |
| EP1858866A1 (en) | Pyroglutamate salts and their use in the optical resolution of intermediates for the synthesis of dextrocetirizine and levocetirizine | |
| CA1193601A (en) | Indanone-oxyalkyl-piperazine derivatives, their preparation, and pharmaceutical formulations containing these compounds | |
| SU343574A1 (en) | METHOD OF OBTAINING 2-HLOR-10- [ | |
| PL163415B1 (en) | Method of obtaining 2-[2-[4-[/4-chlorophenyl/phenylmethyl]-1-piperazinyl] ethoxy] acetic acid and its dihydrohloride | |
| KR870000865B1 (en) | Prpeparation process of substituted benzoic acid derivatives | |
| JPH0625158B2 (en) | Process for producing 1- (2-pyrimidyl) piperazines | |
| NO167975B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINOPROPANOLE DERIVATIVES OF 3- (3-HYDROXYPHENYL) -1-PROPANONE COMPOUNDS. | |
| JPH09268181A (en) | Production of optically active 2-methylpiperazine | |
| SE178089C1 (en) | ||
| JPH0429987A (en) | Production of 1, 3-oxathiolane compound | |
| JPS6025989A (en) | Preparation of furfuryl alcohol derivative |