WO2004065375A1 - Processes for the preparation of escitalopram and its precursor - Google Patents
Processes for the preparation of escitalopram and its precursor Download PDFInfo
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- WO2004065375A1 WO2004065375A1 PCT/IN2003/000220 IN0300220W WO2004065375A1 WO 2004065375 A1 WO2004065375 A1 WO 2004065375A1 IN 0300220 W IN0300220 W IN 0300220W WO 2004065375 A1 WO2004065375 A1 WO 2004065375A1
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- Prior art keywords
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- 238000000034 method Methods 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 title claims abstract description 32
- 229960004341 escitalopram Drugs 0.000 title claims abstract description 32
- 239000002243 precursor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- IUSPXLCLQIZFHL-UHFFFAOYSA-N 5-bromo-3h-2-benzofuran-1-one Chemical compound BrC1=CC=C2C(=O)OCC2=C1 IUSPXLCLQIZFHL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 6
- 238000002955 isolation Methods 0.000 claims abstract description 6
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 138
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 23
- NTOIKDYVJIWVSU-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000006184 cosolvent Substances 0.000 claims description 12
- -1 oxalate Chemical class 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 150000008366 benzophenones Chemical class 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- NGPAITITALWALP-UHFFFAOYSA-M magnesium;n,n-dimethylpropan-1-amine;chloride Chemical compound [Mg+2].[Cl-].CN(C)CC[CH2-] NGPAITITALWALP-UHFFFAOYSA-M 0.000 claims description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 150000001923 cyclic compounds Chemical class 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 2
- 150000007513 acids Chemical class 0.000 claims 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 7
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 4
- 239000003495 polar organic solvent Substances 0.000 abstract 1
- 239000011541 reaction mixture Substances 0.000 description 44
- 239000010410 layer Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 15
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 229960001653 citalopram Drugs 0.000 description 13
- 239000007787 solid Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- XEEGWTLAFIZLSF-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carbonitrile Chemical compound N#CC1=CC=C2C(=O)OCC2=C1 XEEGWTLAFIZLSF-UHFFFAOYSA-N 0.000 description 6
- 239000003610 charcoal Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000000935 antidepressant agent Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- XVNKNFCMXHXIPO-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid;hydrate Chemical compound O.C1=CC(C)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 XVNKNFCMXHXIPO-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- GNAFQJJNHCOBJM-UHFFFAOYSA-N [6-[3-(dimethylamino)propyl]-6-(hydroxymethyl)cyclohexa-2,4-dien-1-yl]methanol Chemical compound CN(CCCC1(C(C=CC=C1)CO)CO)C GNAFQJJNHCOBJM-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 150000001879 copper Chemical class 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 159000000003 magnesium salts Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000003891 oxalate salts Chemical class 0.000 description 2
- SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical class C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 2
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
Definitions
- the present invention relates to an improved process for the preparation of escitalopram.
- Escitalopram is one of the enantiomers of the well-known antidepressant drug, citalopram which [l-((3-dimethylamino)propyl)-l-(4 1 -fluorophenyl)-l,3-dihydro-5-iso- benzofurancarbonitrile] has the formula-I given below:
- This invention also relates to a process for the preparation of an intermediate useful for the preparation of escitalopram.
- Citalopram is a well-known antidepressant drug available in the market for some years. It is a selective, centrally acting serotonin (5-HT) reuptake inhibitor, is accordingly having the antidepressant activity.
- the antidepressant activity of citalopram has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychophannacol. & Biol. Psychiat, 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486.
- the main objective of the present invention is to provide an improved process for the preparation of escitalopram, which is commercially applicable.
- Another objective of the present invention is to provide an improved process for the preparation of escitalopram avoiding the usage of 5-cyanophthalide thereby making the process simple and economical.
- Yet another objective of the present invention is to provide an improved process for the preparation of escitalopram avoiding the purification techniques for the intermediates formed in the process thereby making the process further simpler and economical.
- Still another objective of the present invention is to provide an improved process for the preparation of escitalopram wherein the overall yield is 25-35%.
- di-magnesium salt derived from 5-cyanophthalide will not crystallize out from the reaction mixture under above-mentioned conditions (usage of non-polar co-solvent in Grignard reaction) for its bromo-analogue.
- the crystallization property to the di-magnesium salt of the formula-XII seems to be specific.
- the usage of a co-solvent in the double Grignard reaction on 5- bromophthalide and identification of crystalline property to the resulting di-magnesium salt and its isolation by filtration to get pure compound of the formula- XII is the novelty of the invention. Crystalline property of the resulting di-magnesium salt has not been identified earlier and also it has not been isolated.
- the Grignard reaction in steps (i) and (ii) may be effected at a temperature in the range of -25°C to 0°C preferably at a temperature in the range of -20°C to -10°C.
- the non-polar co-solvent used in steps (i) and (ii) may be benzene, toluene, cyclohexane, etc., preferably toluene or cycohexane.
- the neutralization reagent used in step (iii) may be organic or mineral acid.
- the organic acid can be acetic acid, propionic acid, oxalic acid, succinic acid, ammonium chloride, etc.
- the mineral acid can be hydrochloric acid, sulfuric acid, etc.
- the solvent used in resolution step may be methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, or a mixture thereof.
- the solvent used in cyclization step may be methylene chloride, toluene, cyclohexane, tetrahydrofuran, isopropyl ether, ether, acetonitrile, etc.
- the cyanation step may be done in N,N- dimethylformamide, N,N-dimethylacetamide, pyridine, N-methyl-2-pyrrolidone, etc.
- the pharmaceutically acceptable oxalate salt formation can be done in solvents like, methanol, ethanol, isopropanol, water, acetone, acetonitrile, or a mixture thereof.
- the Grignard solution prepared from 90gr of 4-fiuorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5- bromophthalide (lOOgr) in THF (400ml) at -15 to -10°C under nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at same temperature for another 3hrs.
- the second Grignard reagent prepared from 68gr of 3- (dimethylamino)propyl chloride and 16gr of magnesium turnings in THF (300ml) and toluene (300ml) was added to the above reaction mixture at -15 to 0°C over a period of 2- 3hrs and maintained for additional lhr.
- the solid di-magnesium compound of formula-XLI obtained above was suspended in 1000ml of water and treated with lOOgr of ammonium chloride. After stirring for 30min, product was extracted into toluene (1 x 500ml, 2 x 200ml) and the combined organic layer treated with lOgr of active charcoal. Toluene was distilled off from the reaction mixture below 60°C and to the residue di-isaopropyl ether was added. The crystalline compound of formula-IV was isolated by filtration to get 130gr (70% based on 5- bromophthalide). Melting point: 118-120°C. Purity by HPLC: 98.5%.
- the dihydroxy compound of formula-IV (lOOgr) was dissolved in 300ml of isopropyl alcohol at 40-45°C.
- Solid (+)-di-p-toluoyltartaric acid monohydrate (50gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C.
- the crystals formed in the reaction mixture were filtered and washed with 50ml of isopropyl alcohol to get 55gr (74%) of (-)-4-bromo- ⁇ 1 -(4-fluorophenyl)- ⁇ 1 -[3-(dimethylamino)propyl]- 1,2-benzenedimethanol, hemi (+)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C.
- the Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5- bromophthalide (lOOgr) in THF (400ml) at -15 to -10°C under nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at same temperature for another 3hrs.
- the second Grignard reagent prepared from 68gr of 3- (dimethylamino)propyl chloride and 16gr of magnesium turnings in THF (300ml) and cyclohexane (300ml) was added to the above reaction mixture at -15 to 0°C over a period of 2-3hrs and maintained for additional lhr.
- the solid di-magnesium compound of formula-XII obtained above was suspended in 1000ml of water and treated with lOOgr of ammonium chloride. After stirring for 30min, product was extracted into ethyl acetate (1 x 500ml, 2 x 200ml) and the combined organic layer treated with lOgr of active charcoal. Ethyl acetate was distilled off from the reaction mixture below 50°C and to the residue di-isopropyl ether and hexane were added. The crystalline compound of formula-IV was isolated by filtration to get 75gr. Melting point: 117-120°C. Purity by HPLC: 98%.
- the dihydroxy compound of formula-IV (70gr) was dissolved in 210ml of isopropyl alcohol at 40-45°C.
- Solid (+)-di-p-toluoyltartaric acid monohydrate (35gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C.
- the crystals formed in the reaction mixture were filtered and washed with 30ml of isopropyl alcohol to get 30gr (58%) of (-)-4-bromo- 1 -(4-fluorophenyl)- ⁇ 1 -[3-(dimethylamino)propyl]- 1,2-benzenedimethanol, hemi (+)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C.
- Escitalopram of formula-I can be prepared in a simple and easy to adopt manner without involving any tedious purification steps.
- Escitalopram of formula-I can be prepared in >25% yield, which is better than the earlier known process.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to an improved process for the preparation of escitalopram of the formula-I which consists of a sequential double Grignard reaction on 5-bromophthalide, isolation of di-magnesium salt, neutralization of di-magnesium salt, resolution of dihydroxy compound of the formula-IV and cyclization of resolved compound of the formula-IV, cyanation of compound of the formula-IV using DMF and copper(I)cyanide. The present process utilizes the insoluble property of di-magnesium salt of formula-XII in a mixture of THF and a non-polar organic solvent and separates it from impurities by simple filtration thereby making the isolation and purification process simple.
Description
PROCESSES FOR THE PREPARATION OF ESCITALOPRAM ND ITS PRECURSOR
The present invention relates to an improved process for the preparation of escitalopram. Escitalopram is one of the enantiomers of the well-known antidepressant drug, citalopram which [l-((3-dimethylamino)propyl)-l-(41-fluorophenyl)-l,3-dihydro-5-iso- benzofurancarbonitrile] has the formula-I given below:
This invention also relates to a process for the preparation of an intermediate useful for the preparation of escitalopram.
BACKGROUND OF THE INVENTION:
Citalopram is a well-known antidepressant drug available in the market for some years. It is a selective, centrally acting serotonin (5-HT) reuptake inhibitor, is accordingly having the antidepressant activity. The antidepressant activity of citalopram has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychophannacol. & Biol. Psychiat, 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486.
The process for the preparation of antidepressant citalopram and its pharmaceutoical properties were first disclosed in DE Patent no. 2,657,013 (1977) corresponding to US Patent no. 4,136,193 (1979). Subsequently it was also disclosed in GB patent no.1,526,331 (1978).
The basic process for the preparation of citalopram described in the above-referred patents involves two major routes illustrated in Scheme- 1 and Scheme-2. Major difference in these two routes is introduction of dimethylaminopropyl side chain at an early stage (Scheme- 1) or at a later stage (Scheme- 2).
In the first route, 5-bromophthalide of the formula-II is reacted with p-fluorophenyl- magnesium bromide to get a benzophenone derivative of the formula-iπ. This benzophenone derivative is reacted with 3-(dimethylamino)propylmagnesium chloride to
Scheme- 1
Cyclization of the compound of the formula-IV with an acid catalyst resulted in the formation of phthalane derivative of the formula-V. This bromophthalane derivative is reacted with copper (I) cyanide to get the citalopram base of the formula-I.
In the second route, 5-bromophthalide of the formula-II is reacted with p-fluorophenyl- magnesium bromide to get the corresponding benzophenone derivative of the formula-Ill.
Scheme-2
This compound of the formula-Ill is reduced with lithium aluminum hydride to get the dihydroxy compound of the formula-VI, which is cyclized with an acid catalyst to get the phthalane derivative of the formula- VII. The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base of the formula-I.
Another method for the preparation of citalopram base of the formula-I and an intermediate useful for the preparation of citalopram was described in U S. Pat. No. 4,650,884, according to which 5-cyanophthalide of formula-IX is reacted successively with p-fluorophenylmagnesium bromide and 3-(dimethylamino)propylmagnesium chloride to get the compound of the formula-XI which is reacted with 70% sulfuric acid to get the citalopram base (Scheme-3).
Scheme-3
Process for the preparation of escitalopram is disclosed in U. S. Pat. No. 4,943,590. According to this patent, attempts to crystallize the diastereomeric salts of citalopram enantiomers have failed. In this patent a process for the preparation of escitalopram was described by resolving the intermediate (compound of the formula-XI) of citalopram and
ring closure of the resolved intermediate in a stereospecific manner to get the escitalopram (Scheme-4).
(+)-di-p-toluoyltartaric acid
(+)-di-p-toluoyltartaric acid and (-)-XI salt
IPA
Scheme-4 The main drawback in this process is the purity of the intermediate compound of the formula-XI obtained in the Grignard reaction, which is of 80-90% only. The crude compound of formula-XI needs extensive purification before proceeding for resolution. The purification technique given in the above patent process involves repeated charcoal and silica gel treatment to the compound of the formula-XI or its HBr salt. Also, during the HBr salt formation of compound of the formula-XI, the amount of HBr used in the process should be less than the molar quantity to avoid additional impurities formation. As the impurities present in the intermediate compound of the formula-XT have closely related properties such a purification technique is not viable on a commercial scale to make this intermediate and also the escitalopram. Also, the overall yield of escitalopram given in this patent is only 8.8% starting from 5-cyanophthalide of the formula-IX.
Therefore such a low yielding process needs to be improved for commercial production of escitalopram.
Keeping in view of the difficulties in commercialization of the above-mentioned process for the preparation of escitalopram, we aimed to develop a simple and economical process for commercial production of escitalopram.
We observed that a promising approach for a process for the preparation of escitalopram will be to (a) avoid the usage of 5-cyanophthalide as starting material (b) avoid the purification of intermediates involved in making escitalopram thereby making the process commercially viable and economical.
Accordingly the main objective of the present invention is to provide an improved process for the preparation of escitalopram, which is commercially applicable.
Another objective of the present invention is to provide an improved process for the preparation of escitalopram avoiding the usage of 5-cyanophthalide thereby making the process simple and economical.
Yet another objective of the present invention is to provide an improved process for the preparation of escitalopram avoiding the purification techniques for the intermediates formed in the process thereby making the process further simpler and economical.
Still another objective of the present invention is to provide an improved process for the preparation of escitalopram wherein the overall yield is 25-35%.
As an alternative process for the preparation of escitalopram disclosed in the above mentioned prior art patent, we looked particularly into the original process developed by Lundbeck for dl-citalopram (Scheme-I above). In this route, the bromo-analogue (compound of the formula-IV) of the intermediate compound of the formula-XI can be separated into its enantiomers by conventional resolution techniques (preferential
crystallization of diastereomeric salts) and converted into escitalopram. However, in the original process for the preparation of compound of the formula-IV no purity has been mentioned. It only says that the intermediate compound of the formula-IV is prepared in an analogous manner. The yield given for the analogous compound of the formula-IV is only 55%. Therefore, such a process needs to be improved with respect to the yield of the compound of the formula-IV and its quality for its commercial usage in making escitalopram. Also, the compound of formula-IV is described as an oil.
Surprisingly, we have found that if one does the sequential double Grignard reaction on 5-bromophthalide analogous to 5-cyanophthalide in tetrahydrofuran medium along with a non-polar co-solvent, the resulting magnesium salt (compound of the formula-XII) crystallizes from the reaction mass leaving all the related impurities in the reaction medium. The crystalline magnesium salt can be simply filtered off from the reaction mass and neutralized to get the pure compound of the formula-TV, an analogue of the compound of the formula-XI used in the known process for escitalopram. Although compound of the formula-IV is known, isolation of its magnesium salt in a pure form to get a pure product of the formula-IV is not known. We also found that di-magnesium salt derived from 5-cyanophthalide will not crystallize out from the reaction mixture under above-mentioned conditions (usage of non-polar co-solvent in Grignard reaction) for its bromo-analogue. The crystallization property to the di-magnesium salt of the formula-XII seems to be specific. The usage of a co-solvent in the double Grignard reaction on 5- bromophthalide and identification of crystalline property to the resulting di-magnesium salt and its isolation by filtration to get pure compound of the formula- XII is the novelty of the invention. Crystalline property of the resulting di-magnesium salt has not been identified earlier and also it has not been isolated. Such a crystalline property to the di- magnesium salt of the formula-XII in a mixture of tetrahydrofuran and a non-polar solvent eliminated all the unwanted impurities after filtering off the di-magnesium salt of the compound of formula-XII from the reaction mass. The dihydroxy compound of the formula-IV obtained by this process was found to be pure and crystalline and the yield was 70-75% of theory.
The reaction scheme is illustrated below:
XII (Isolated) IV
(+)-di-p-toluoyltartaric acid *- (+)-di-p-toluoyltartaric acid and (-)-IV salt
IPA
Scheme-5
Accordingly the present invention provides an improved process for the preparation of escitalopram of the formula-I,
(i) reacting 5-bromophthalide of the formula-II,
II with p-fluorophenylmagnesium bromide in THF medium with a non-polar co- solvent to get the benzophenone derivative of the formula-Ill,
(iii) Isolating the crystalline compound of the formula-XII by filtration and neutralizing the di-magnesium salt to get the dihydroxy compound of the formula-IV,
(iv) Resolving the compound of the formula-IV with (+)-di-p-toluoyltartaric acid by preferential crystallization to get its (-)-enatiomer salt with (+)-di-p- toluoyltartaric acid (v) Neutralizing the diastereomeric salt and reacting the liberated chiral base with methanesulfonyl chloride in basic medium to get the cyclic compound of the formula-V,
(vi) Reacting the compound of the formula-V with copper cynanide to get the chiral compound of the formula-I.
(vii) and if desired converting the compound of the formula-I into its pharmaceutically acceptable salt, like oxalate, etc by conventional methods.
According to another feature of the invention there is provided an improved process for the preparation of the intermediate compound of the formula-XII ,in a crystalline form
(i) reacting 5-bromophthalide of the formula-II,
with p-fluorophenylmagnesium bromide in THF medium with a non-polar co- solvent to get the benzophenone derivative of the formula-Ill,
(ii) reacting the benzophenone derivative of the formula-Ill with 3- (dimethylamino)propylmagnesium chloride to get the crystalline di- magnesium salt of formula-XII,
(iii) and Isolating the crystalline compound of the formula-XII by filtration.
The Grignard reaction in steps (i) and (ii) may be effected at a temperature in the range of -25°C to 0°C preferably at a temperature in the range of -20°C to -10°C. The non-polar
co-solvent used in steps (i) and (ii) may be benzene, toluene, cyclohexane, etc., preferably toluene or cycohexane. The neutralization reagent used in step (iii) may be organic or mineral acid. The organic acid can be acetic acid, propionic acid, oxalic acid, succinic acid, ammonium chloride, etc. The mineral acid can be hydrochloric acid, sulfuric acid, etc. The solvent used in resolution step may be methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, or a mixture thereof. The solvent used in cyclization step may be methylene chloride, toluene, cyclohexane, tetrahydrofuran, isopropyl ether, ether, acetonitrile, etc. The cyanation step may be done in N,N- dimethylformamide, N,N-dimethylacetamide, pyridine, N-methyl-2-pyrrolidone, etc.
The pharmaceutically acceptable oxalate salt formation can be done in solvents like, methanol, ethanol, isopropanol, water, acetone, acetonitrile, or a mixture thereof.
The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention
Example 1
Preparation of escitalopram:
(i) Preparation of di-magnesium salt of formula-XII:
The Grignard solution prepared from 90gr of 4-fiuorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5- bromophthalide (lOOgr) in THF (400ml) at -15 to -10°C under nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at same temperature for another 3hrs. The second Grignard reagent prepared from 68gr of 3- (dimethylamino)propyl chloride and 16gr of magnesium turnings in THF (300ml) and toluene (300ml) was added to the above reaction mixture at -15 to 0°C over a period of 2- 3hrs and maintained for additional lhr. TLC of the reaction mixture showed the absence of starting material. Slowly the reaction mixture was allowed to rise to 10°C and filtered
the salts. The wet cake was washed with 200ml of toluene and air dried to get 210gr of free-flowing white crystalline solid di-magnesiufn salt of formula-XII.
(ii) Preparation of dihydroxy compound of formula-IV:
The solid di-magnesium compound of formula-XLI obtained above was suspended in 1000ml of water and treated with lOOgr of ammonium chloride. After stirring for 30min, product was extracted into toluene (1 x 500ml, 2 x 200ml) and the combined organic layer treated with lOgr of active charcoal. Toluene was distilled off from the reaction mixture below 60°C and to the residue di-isaopropyl ether was added. The crystalline compound of formula-IV was isolated by filtration to get 130gr (70% based on 5- bromophthalide). Melting point: 118-120°C. Purity by HPLC: 98.5%. 1H-NMR (CDC13, 200MHz): 7.39-7.44 (m, 2H, ar. H), 7.25-7.34 (m, 3H, ar. H), 6.90-7.00 (m, 2H, ar. H), 4.33 (d, J = 12.0Hz, 1H, -CH2OH), 4.06 (d, J = 11.7Hz, 1H, -CH2OH), 2.46-2.54 (m, 4H, -CH2CH2CH2-), 2.22 (s, 6H, 2 x NCH3), and 1.51-1.75 (m, 2H, -CH2CH2CH2-).
(iii) Resolution of dihydroxy compound of formula-IV:
The dihydroxy compound of formula-IV (lOOgr) was dissolved in 300ml of isopropyl alcohol at 40-45°C. Solid (+)-di-p-toluoyltartaric acid monohydrate (50gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C. The crystals formed in the reaction mixture were filtered and washed with 50ml of isopropyl alcohol to get 55gr (74%) of (-)-4-bromo-α1-(4-fluorophenyl)- α1-[3-(dimethylamino)propyl]- 1,2-benzenedimethanol, hemi (+)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C.
The above salt (50gr) was suspended in 150ml of isopropyl alcohol and heated to 70°C. The resulting suspension was maintained at 70°C for lhr and cooled to 25-30°C. The solids were filtered off and dried to yield 45gr of above salt. Chiral purity by HPLC is 99.4%. Melting point: 128-130°C. [α]D = +7.49° (c = 1, methanol).
(iv) Cyclization of resolved dihydroxy compound of formula-IV:
To 72gr of (-)-4-bromo- 1-(4-fluorophenyl)- α1-[3-(dimethylamino)propyl]-l,2-benzene- dimethanol, hemi (+)-di-p-toluoyltartaric acid salt in 720ml of water was added a solution
of 11.5gr of sodium hydroxide in 140ml of water. After stirring for lhr at 25-30°C product was extracted into toluene (1 x 300ml, 2 x 100ml) and the toluene layer distilled off below 60°C to get 46.0gr (95%) of the (-)-isomer of dihydroxy compound as oil. [O.]D = -50.98° (c = 1, methanol).
To a solution of the above base in toluene (700ml) was added triethylamine (34.2gr) and cooled to -5°C. Methanesulfonyl chloride (17.8gr) was slowly added to the reaction mixture at -5 to 0°C over a period of 3hrs. After maintaining for lhr at same temperature reaction was found to complete by TLC. The reaction mixture was poured into water (350ml) and separated toluene layer. Aqueous layer was extracted with toluene (2 x 50ml) and the combined toluene layer washed with 200ml of water. Toluene was distilled off from the reaction mixture below 60°C to get 40gr (91%). [α]D = +2.0° (c = 1, methanol). Chiral purity by HPLC: 99.2%.
A small sample (5.0gr) was converted to its oxalate salt in acetone medium. Melting point: 160-162°C. [α]D = +2.2° (c = 1, methanol). Chiral purity by HPLC: 99.5%.
(v) Cyanation of bromo compound of formula- VI:
To a solution of bromo compound (lOOgr) of formula- VI in DMF (1000ml) was added copper(I)cyanide (31.0gr) and the reaction mixture heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 8hrs, reaction mixture was cooled to 25-30°C and poured into water (3000ml). After stirring for lhr, ethylenediamine (100ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring. Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid hiflow. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (200ml and 100ml). The combined acetic acid layer was treated with charcoal (lOgr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x
300ml, 2 x 100ml) and the solvent distilled off to get 60gr (70%) of crude escitalopram base as oil. Purity by HPLC was found to be >97%. Chiral purity by HPLC is 99.2%.
Example 2
Preparation of escitalopram:
(i) Preparation of di-magnesium salt of formula-XII:
The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5- bromophthalide (lOOgr) in THF (400ml) at -15 to -10°C under nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at same temperature for another 3hrs. The second Grignard reagent prepared from 68gr of 3- (dimethylamino)propyl chloride and 16gr of magnesium turnings in THF (300ml) and cyclohexane (300ml) was added to the above reaction mixture at -15 to 0°C over a period of 2-3hrs and maintained for additional lhr. TLC of the reaction mixture showed the absence of starting material. Slowly the reaction mixture was allowed to rise to 10°C and filtered the salts. The wet cake was washed with 200ml of cyclohexane and air dried to get 165gr of free-flowing white crystalline solid di-magnesium salt of formula-XII.
(ii) Preparation of dihydroxy compound of formula-IV:
The solid di-magnesium compound of formula-XII obtained above was suspended in 1000ml of water and treated with lOOgr of ammonium chloride. After stirring for 30min, product was extracted into ethyl acetate (1 x 500ml, 2 x 200ml) and the combined organic layer treated with lOgr of active charcoal. Ethyl acetate was distilled off from the reaction mixture below 50°C and to the residue di-isopropyl ether and hexane were added. The crystalline compound of formula-IV was isolated by filtration to get 75gr. Melting point: 117-120°C. Purity by HPLC: 98%.
(iii) Resolution of dihydroxy compound of formula-IV:
The dihydroxy compound of formula-IV (70gr) was dissolved in 210ml of isopropyl alcohol at 40-45°C. Solid (+)-di-p-toluoyltartaric acid monohydrate (35gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C. The crystals
formed in the reaction mixture were filtered and washed with 30ml of isopropyl alcohol to get 30gr (58%) of (-)-4-bromo- 1-(4-fluorophenyl)- α1-[3-(dimethylamino)propyl]- 1,2-benzenedimethanol, hemi (+)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C.
The above salt (30gr) was suspended in 100ml of isopropyl alcohol and heated to 70°C. The resulting suspension was maintained at 70°C for lhr and cooled to 25-30°C. The solids were filtered off and dried to yield 26gr of above salt. Chiral purity by HPLC is 99.5%. Melting point: 128-130°C. [α]D = +7.4° (c = 1, methanol).
(iv) Cyclization of resolved dihydroxy compound of formula-IV:
To 25gr of (-)-4-bromo-α1-(4-fluorophenyl)- α1-[3-(dimethylamino)propyl]-l,2-benzene- dimethanol, hemi (+)-di-p-toluoyltartaric acid salt in 250ml of water was added a solution of 4.0gr of sodium hydroxide in 50ml of water. After stirring for lhr at 25-30°C product was extracted into toluene (1 x 100ml, 2 x 30ml) and the toluene layer distilled off below 60°C to get 16.5gr of the (-)-isomer of dihydroxy compound as oil. [O.]D = -51.0° (c = 1, methanol).
To a solution of the above base in toluene (200ml) was added triethylamine (11.2gr) and cooled to -5°C. Methanesulfonyl chloride (6.0gr) was slowly added to the reaction mixture at -5 to 0°C over a period of 3hrs. After maintaining for lhr at same temperature reaction was found to complete by TLC. The reaction mixture was poured into water (100ml) and separated toluene layer. Aqueous layer was extracted with toluene (2 x 25ml) and the combined toluene layer washed with 75ml of water. Toluene was distilled off from the reaction mixture below 60°C to get an oil (15.0gr). [α]o = +1.8° (c = 1, methanol). Chiral purity by HPLC: 99.0%.
(v) Cyanation of bromo compound of formula- VI:
To a solution of bromo compound (30gr) of formula- VI in pyridine (25ml) was added copper(I)cyanide (9.0gr) and the reaction mixture heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 8hrs, reaction mixture was cooled to 25-30°C and poured into water (250ml). After stirring for lhr,
ethylenediamine (30ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring. Toluene (100ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid hiflow. The hiflow bed was washed with 100ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (100ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (100ml and 50ml). The combined acetic acid layer was treated with charcoal (5gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 100ml, 2 x 50ml) and the solvent distilled off to get the crude escitalopram base (18gr). Purity by HPLC was found to be >96%. Chiral purity by HPLC is 99.0%.
Example 3
Preparation of (-)-isomer of citalopram:
(i) Resolution of dihydroxy compound of formula-TV:
The dihydroxy compound of formula-IV (lOOgr) was dissolved in 300ml of isopropyl alcohol at 40-45°C. Solid (-)-di-p-toluoyltartaric acid monohydrate (50gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C. The crystals formed in the reaction mixture were filtered and washed with 50ml of isopropyl alcohol to get 50gr (67%) of (+)-4-bromo-α1-(4-fluorophenyl)- α1-[3-(dimethylamino)propyl]- 1,2-benzenedimethanol, hemi (-)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C
The above salt (50gr) was suspended in 150ml of isopropyl alcohol and heated to 70°C. The resulting suspension was maintained at 70°C for lhr and cooled to 25-30°C. The solids were filtered off and dried to yield 40gr of above salt. Chiral purity by HPLC is 99.4%. Melting point: 128-130°C. [α]D = -8.3° (c = 1, methanol).
(ii) Cyclization of resolved dihydroxy compound of formula-IV:
To 40gr of (+)-4-bromo-α1-(4-fluorophenyl)- α1-[3-(dimethylamino)propyl]-l,2- benzene-dimethanol, hemi (-)-di-p-toluoyltartaric acid salt in 400ml of water was added a solution of 3.5gr of sodium hydroxide in 40ml of water. After stirring for lhr at 25-30°C
product was extracted into toluene (1 x 100ml, 2 x 50ml) and the toluene layer distilled off below 60°C to get 26gr of the (+)-isomer of dihydroxy compound as oil. [O.]D = +52.0° (c = l, methanol).
To a solution of the above base in toluene (300ml) was added triethylamine (18gr) and cooled to -5°C. Methanesulfonyl chloride (9.1gr) was slowly added to the reaction mixture at -5 to 0°C over a period of 3hrs. After maintaining for lhr at same temperature reaction was found to complete by TLC. The reaction mixture was poured into water (250ml) and separated toluene layer. Aqueous layer was extracted with toluene (2 x 50ml) and the combined toluene layer washed with 100ml of water. Toluene was distilled off from the reaction mixture below 60°C to get an oil (17.0gr). [O.]D = -2.4° (c = 1, methanol). Chiral purity by HPLC: 99.4%.
(iii) Cyanation of bromo compound of formula- VI:
To a solution of bromo compound (lO.Ogr) of formula- VI in DMF (100ml) was added copper(I)cyanide (3.1gr) and the reaction mixture heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 8hrs, reaction mixture was cooled to 25-30°C and poured into water (300ml). After stirring for lhr, ethylenediamine (10ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring. Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid hiflow. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (50ml). The acetic acid layer was treated with charcoal (2gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (2 x 50ml) and the solvent distilled off to get the crude (-)-citalopram base (5.0gr). Purity by HPLC was found to be >97%. Chiral purity by HPLC is 99.3%.
Advantages of the present invention:
1. Escitalopram of formula-I can be prepared in a simple and easy to adopt manner without involving any tedious purification steps.
2. Escitalopram of formula-I can be prepared in >25% yield, which is better than the earlier known process.
3. An improved process for the preparation of the intermediate compound of the formula-IV.
4. The present process produces pure (>99.8%) enantiomeric forms of the intermediates of the formulae-IV and V or its salts.
5. The present process produces pure (>98%) di-magnesium salt of intermediate compound of the formula-XII, which is not isolated earlier.
Claims
1. An improved process for the preparation of escitalopram of the formula-I,
with p-fluorophenylmagnesium bromide in THF medium with a non-polar co- solvent to get the benzophenone derivative of formula-Ill,
(iii) Isolating the crystalline compound of the formula-XII by filtration and neutralizing the di-magnesium salt to get the dihydroxy compound of the formula-IV,
(iv) Resolving the compound of the formula-IV with (+)-di-p-toluoyltartaric acid by preferential crystallization to get its (-)-enatiomer salt with (+)-di-p- toluoyltartaric acid
(v) Liberating the chiral base from the diasteromeric salt by neutralization and reacting the liberated chiral base with methanesulfonyl chloride in basic medium to get the cyclic compound of the formula-V,
(vi) Reacting the compound of the formula-V with copper cynanide to get the chiral compound of the formula-I. (vii) and if desired converting the compound of the formula-I into its pharmaceutically acceptable salt, like oxalate, etc by conventional methods.
2. An improved process as claimed in claim 1 wherein the Grignard reaction in steps (i) and (ii) is effected at a temperature in the range of -25°C to 0°C, preferably at -20°C to - 10°C.
3. An improved process as claimed in claims 1 & 2 wherein the non-polar co-solvent used in steps (i) and (ii) is selected from benzene, toluene, cyclohexane, etc, preferably toluene or cyclohexane.
4. An improved process as claimed in claims 1 to 3 wherein the ratio between THF and non-polar co-solvent used in steps (i) and (ii) is in the range of 3 -6 : 1 -3 , preferably 4:1.
5. An improved process as claimed in claim 1 to 4 wherein the neutralization reagent used in step (iii) is selected from acids like acetic acid, propionic acid, oxalic acid, succinic acid, ammonium chloride, etc., preferably acetic acid or ammonium chloride.
6. An improved process as claimed in claim 1 to 5 wherein the mineral acid used for neutralization is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, etc., preferably hydrochloric acid or hydrobromic acid.
7. An improved process as claimed in claim 1 to 6 wherein the solvent used in resolution step is selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, preferably, ethanol, isopropanol or ethyl acetate.
8. An improved process as claimed in claim 1 to 7 wherein the solvent used in cyclization step is selected from methylene chloride, toluene, cyclohexane, tetrahydrofuran, isopropyl ether, ether, acetonitrile, etc., preferably, methylene chloride, toluene or cyclohexane.
9. An improved process as claimed in claim 1 to 8 wherein the base used in cyclization step is selected from a tertiary amine like, triethylamine, tributylamine, pyridine, etc., preferably, triethylamine or pyridine.
10. An improved process as claimed in claim 1 to 9 wherein the cyanation step is done in N,N-dimethylforrnamide, N,N-dimethylacetamide, pyridine, N-methyl-2-pyrrolidone, etc., preferably, N,N-dimethylformamide, pyridine or N-methyl-2-pyrrolidone.
11. An improved process for the preparation of escitaslopram of formula-I and its pharmaceutically acceptable salts substantially as described herein with reference to the Examples.
12. An improved process for the preparation of the intermediate compound of the formula-XII in a crystalline form
B
(i) reacting 5-bromophthalide of the formula-II,
II with p-fluorophenylmagnesium bromide in THF medium with a non-polar co- solvent to get the benzophenone derivative of the formula-ϋl, 
(ii) reacting the benzophenone derivative of the formula-Ill with 3- (dimethylamino)propylmagnesium chloride to get the crystalline di- magnesium salt of formula-XII,
(iii) and isolating the crystalline compound of the formula-XII by filtration.
13. A process as claimed in claim 12 wherein the Grignard reaction in steps (i) and (ii) is effected at a temperature in the range of -25°C to 0°C, preferably -20°C to -10°C.
14. A process as claimed in claim 12 and 13 wherein the non-polar co-solvent used in steps (i) and (ii) is selected from benzene, toluene, cyclohexane, etc, preferably toluene or cyclohexane.
15. A process as claimed in claims 12 to 14 wherein the ratio between THF and non- polar co-solvent used in steps (i) and (ii) is in the range of 3-6: 1-3, preferably 4: 1.
16. A process as claimed in claim 12 to 15 wherein the filtration temperature for the isolation of the compound of the formula-XII is in the range of 0-40°C preferably, in the range of 10-25°C.
17. A process for the preparation of both the enantiomers of compound of formula-IV or its acid addition salts as claimed in claim 1 to 11.
18. A process for the preparation of both the enantiomers of compound of formula-V or its acid addition slats as claimed in claim 1 to 11.
19. A process for the preparation of (-)-isomer of compound of formula-I as described in example-3.
20. A Process for the preparation and isolation of compound of the formula-XII, which is an intermediate used in the preparation of escitaslopram of the formula-I, substantially as described in example 1 and 2.
21. A process for the preparation of crystalline compound of formula-IV as claimed in claim 1 to 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003242990A AU2003242990A1 (en) | 2003-01-17 | 2003-06-17 | Processes for the preparation of escitalopram and its precursor |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN52/MAS/2003 | 2003-01-17 | ||
| IN52MA2003 | 2003-01-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004065375A1 true WO2004065375A1 (en) | 2004-08-05 |
Family
ID=32750419
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2003/000220 WO2004065375A1 (en) | 2003-01-17 | 2003-06-17 | Processes for the preparation of escitalopram and its precursor |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003242990A1 (en) |
| WO (1) | WO2004065375A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006025071A1 (en) * | 2004-09-02 | 2006-03-09 | Natco Pharma Limited | A process for the preparation of escitalopram |
| WO2006106531A1 (en) * | 2005-04-04 | 2006-10-12 | Jubilant Organosys Ltd | Process for the preparation of escitalopram or its acid addition salts |
| EP2017271A1 (en) * | 2007-07-06 | 2009-01-21 | Aurobindo Pharma Limited | Process for the preparation of escitalopram |
| EA012787B1 (en) * | 2007-09-11 | 2009-12-30 | Х. Лундбекк А/С | Method for the preparation of escitalopram |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4136193A (en) * | 1976-01-14 | 1979-01-23 | Kefalas A/S | Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans |
| US4650884A (en) * | 1984-08-06 | 1987-03-17 | H. Lundbeck A/S | Novel intermediate and method for its preparation |
| WO2003029236A1 (en) * | 2001-09-24 | 2003-04-10 | Pharmachem Technologies Limited | Process for the preparation of citalopram |
-
2003
- 2003-06-17 AU AU2003242990A patent/AU2003242990A1/en not_active Abandoned
- 2003-06-17 WO PCT/IN2003/000220 patent/WO2004065375A1/en not_active Application Discontinuation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4136193A (en) * | 1976-01-14 | 1979-01-23 | Kefalas A/S | Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans |
| US4650884A (en) * | 1984-08-06 | 1987-03-17 | H. Lundbeck A/S | Novel intermediate and method for its preparation |
| WO2003029236A1 (en) * | 2001-09-24 | 2003-04-10 | Pharmachem Technologies Limited | Process for the preparation of citalopram |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006025071A1 (en) * | 2004-09-02 | 2006-03-09 | Natco Pharma Limited | A process for the preparation of escitalopram |
| WO2006106531A1 (en) * | 2005-04-04 | 2006-10-12 | Jubilant Organosys Ltd | Process for the preparation of escitalopram or its acid addition salts |
| EP2017271A1 (en) * | 2007-07-06 | 2009-01-21 | Aurobindo Pharma Limited | Process for the preparation of escitalopram |
| EA012787B1 (en) * | 2007-09-11 | 2009-12-30 | Х. Лундбекк А/С | Method for the preparation of escitalopram |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003242990A1 (en) | 2004-08-13 |
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