WO2014199313A1 - Chlorhydrate de vilazodone sensiblement pur et son procédé de préparation - Google Patents
Chlorhydrate de vilazodone sensiblement pur et son procédé de préparation Download PDFInfo
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- WO2014199313A1 WO2014199313A1 PCT/IB2014/062132 IB2014062132W WO2014199313A1 WO 2014199313 A1 WO2014199313 A1 WO 2014199313A1 IB 2014062132 W IB2014062132 W IB 2014062132W WO 2014199313 A1 WO2014199313 A1 WO 2014199313A1
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- Prior art keywords
- formula
- compound
- process according
- vilazodone
- solution
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 47
- RPZBRGFNBNQSOP-UHFFFAOYSA-N vilazodone hydrochloride Chemical compound Cl.C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 RPZBRGFNBNQSOP-UHFFFAOYSA-N 0.000 title abstract description 27
- 229960003381 vilazodone hydrochloride Drugs 0.000 title abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 239000007787 solid Substances 0.000 claims abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 21
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims abstract description 15
- 235000010262 sodium metabisulphite Nutrition 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 13
- 239000002002 slurry Substances 0.000 claims abstract description 11
- 239000004296 sodium metabisulphite Substances 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 8
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 7
- 150000001408 amides Chemical class 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 84
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 17
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 11
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 claims description 2
- 239000002370 magnesium bicarbonate Substances 0.000 claims description 2
- 229910000022 magnesium bicarbonate Inorganic materials 0.000 claims description 2
- 235000014824 magnesium bicarbonate Nutrition 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229960003740 vilazodone Drugs 0.000 abstract description 66
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 abstract description 66
- 239000012535 impurity Substances 0.000 abstract description 30
- 238000002360 preparation method Methods 0.000 abstract description 16
- VLDBEGOSVWUFMW-UHFFFAOYSA-N O=C=C1Cc2cc(ccc2O1)N1CCN(CCCCc2c[nH]c3ccc(cc23)C#N)CC1 Chemical compound O=C=C1Cc2cc(ccc2O1)N1CCN(CCCCc2c[nH]c3ccc(cc23)C#N)CC1 VLDBEGOSVWUFMW-UHFFFAOYSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 43
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 7
- PWUXHCFWVKQNLH-UHFFFAOYSA-N 3-(4-chlorobutyl)-1H-indole-2-carbonitrile Chemical compound ClCCCCC1=C(NC2=CC=CC=C12)C#N PWUXHCFWVKQNLH-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 229940001584 sodium metabisulfite Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 3
- 238000010908 decantation Methods 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 230000005484 gravity Effects 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical compound C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 description 2
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 2
- MMUWHDVLRAINGJ-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;methanesulfonate Chemical compound CS([O-])(=O)=O.C[N+]1=CC=CC=C1Cl MMUWHDVLRAINGJ-UHFFFAOYSA-M 0.000 description 2
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 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
- 239000002253 acid Substances 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LLRGOAFFRRUFBM-UHFFFAOYSA-N 5-piperazin-1-yl-1-benzofuran-2-carboxamide Chemical compound C=1C=C2OC(C(=O)N)=CC2=CC=1N1CCNCC1 LLRGOAFFRRUFBM-UHFFFAOYSA-N 0.000 description 1
- MWHHJYUHCZWSLS-UHFFFAOYSA-N FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F Chemical compound FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F MWHHJYUHCZWSLS-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DBDKAVGLSPIFMP-UHFFFAOYSA-N NC(c1cc(cc(cc2)N3CCN(CCCCc4c[n](CN(CC5)CCN5c5ccc6[o]c(C(N)=O)cc6c5)c(cc5)c4cc5C#N)CC3)c2[o]1)=O Chemical compound NC(c1cc(cc(cc2)N3CCN(CCCCc4c[n](CN(CC5)CCN5c5ccc6[o]c(C(N)=O)cc6c5)c(cc5)c4cc5C#N)CC3)c2[o]1)=O DBDKAVGLSPIFMP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to substantially pure Vilazodone Hydrochloride, process for preparation of the same and also relates to an isolated impurity of Vilazodone.
- Vilazodone hydrochloride can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by product of the reaction, products of side reactions, impurities coming from the starting material or degradation products. It is essential to verify the identity of the source material and to establish its quality otherwise impurities associated with the raw materials may be carried through the manufacturing process to contaminate the final product.
- the process for preparation of Vilazodone illustrated in example-4 of US'241 involves reacting 5-(4-(4-(5- cyano-lH-indol-3-yl)butyl)piperazinyl-l-yl)benzofuran-2-carboxylic acid with 2-chloro-l- methylpyridinium methanesulfonate in the presence of N-methyl pyrrolidine followed by treatment with dried ammonia gas to afford compound of formula I after customary workup.
- the Vilazodone thus obtained was further converted to its hydrochloride salt.
- the experimental procedure of the salification step is not elaborated in the specification.
- Figure - 1 is an illustration of NMR spectrum of compound of formula (5)
- Figure - 2 is an illustration of IR spectrum of compound of formula (5)
- Figure - 3 is an illustration of Mass spectrum of compound of formula (5)
- Figure - 4 is a representative HPLC chromatogram from an analysis of isolated compound of formula (5) labeled as VLZRC-6
- Figure - 5 is a representative HPLC chromatogram from an analysis of pure Vilazodone containing compound of formula (4) and formula (5) labeled as VLZRC-5 and VLZRC-6, respectively. Description of the invention
- the present invention is directed to provide an improved process for preparation and purification of Vilazodone, which when subsequently converted to its hydrochloride provides a substantially pure Vilazodone Hydrochloride free of undesired by-products or impurities.
- the present invention provides an environment friendly cost effective process for obtaining Vilazodone in higher purity and higher yield.
- the crude Vilazodone used in the present invention for purification purpose can be obtained as per a process demonstrated in prior art or by the process of the present invention.
- One aspect of the present invention provides an improved process for the preparation of the crude Vilazodone comprising of condensing 5-(piperaziny-l-yl)-l-benzofuran-2- carboxamide (PBA) of formula (2) with 3-(4-chlrobutyl)-lH-indole-5-carbonitrile (CBCI) of formula (3) in the presence of a condensing agent and solvent. Thereafter the crude Vilazodone is isolated from the reaction mixture by techniques known in the art such as filtration, centrifugation or the like and subjected to purification. The purification process affords the substantially pure Vilazodone of formula (1) which is optionally converted to its pharmaceutically acceptable salts.
- PBA piperaziny-l-yl)-l-benzofuran-2- carboxamide
- CBCI 3-(4-chlrobutyl)-lH-indole-5-carbonitrile
- Another aspect of the present invention provides condensation of compound of formula (2) and formula (3) to obtain compound of formula (1) in the presence of condensing agent and solvent.
- the suitable solvent medium for the reaction is an alcoholic solvent
- alcoholic solvent refers to alcoholic solvent selected from CI to C4 straight or branched chain alcohol containing more than 50% of water, more preferably more than 70% of water or most preferably more than 80% of water.
- the CI to C4 straight or branched chain alcohols include methanol, ethanol, propanol, isopropanol and butanol.
- the preferred alcohol of the present invention is isopropanol.
- the condensing agent is a base selected from a group consisting of inorganic base.
- the suitable inorganic base includes sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, magnesium bicarbonate, calcium carbonate and cesium bicarbonate.
- condensation of compound of formula (2) with compound of formula (3) is carried out at a temperature of about 5 °C to about 110 °C, more preferably at about 25 °C to 90 °C or more preferably at reflux temperature of the reaction mixture.
- the reaction of compound of formula (2) with compound of formula (3) may be carried for about 5 hrs to about 24 hrs, more preferably for about 5 hrs to 12 hrs.
- the crude Vilazodone can be isolated using known techniques in the art such as decantation, filtration by gravity or suction or centrifugation.
- the crude vilazodone obtained by reaction of compound of formula (2) and (3) is slurry washed with water miscible solvent.
- the suitable water miscible solvent may be alcohol such as methanol and ketones such as acetone.
- slurry washing and/or wash and/or washes refers to a agitating a compound with solvent and thereafter isolating the compound by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.
- the process involves purification of crude Vilazodone by charcoalisation of a solution of crude Vilazodone base in an amide solvent such as dimethylformamide(DMF) and N-Methyl pyrrolidine(NMP), followed by treating the filtrate with aqueous sodium metabisulfite, whereupon the pure Vilazodone precipitates which is collected by filtration.
- an amide solvent such as dimethylformamide(DMF) and N-Methyl pyrrolidine(NMP)
- the process involves purification of crude Vilazodone by agitating a solution of crude Vilazodone in an amide solvent such as dimethylformamide (DMF) and N-Methyl pyrrolidine with aqueous sodium metabisulfite and an aqueous inorganic base.
- an amide solvent such as dimethylformamide (DMF) and N-Methyl pyrrolidine
- the process involves purification of crude Vilazodone by agitating a solution of crude Vilazodone in dimethylformamide with aqueous sodium metabisulfite and aqueous inorganic base solution added in combination or separately in sequence.
- aqueous sodium metabisulfite and aqueous inorganic base solution in combination or separately in sequence, is gradually added to solution of crude Vilazodone in dimethylformamide .
- the inorganic base is selected from sodium carbonate, potassium carbonate and cesium carbonate.
- the aqueous inorganic base used in combination with sodium metabisulphite or separately is preferably sodium carbonate.
- the said addition is done in about 15 min. to 90 min., more preferably in 45 min. to 60 min.
- the addition is carried out at a temperature of 5 °C to 60 °C, more preferably at 20 °C to 40 °C and the resulting reaction mixture is stirred for 60-90 min, at 20-35 °C, whereupon the precipitated Vilazodone is collected and washed with water and acetone at ambient temperature to afford pure Vilazodone.
- the compound of formula ( 1 ) obtained by the present invention can be optionally converted into its pharmaceutically acceptable salts, for example hydrochloride salt by any of the method known in the art.
- the Vilazodone hydrochloride salt can be isolated by techniques known in the art such as filtration by gravity or suction, decantation or centrifugation
- the above mentioned production method is employed to prepare compound of formula (1) substantially free of dimer impurity, 5-(4-(4- (5-cyano-l-(4-(5-cyano-lH-indol-3-yl) butyl)- lH-indol-3-yl) butyl) piperazin-l-yl) benzofuran-2-carboxamide, compound of formula (4)
- the process involves purification of crude Vilazodone base involving acid-base treatment of solution of crude Vilazodone base in an amide solvent, which is preferably dimethylformamide ( DMF) before treatment with aqueous sodium metabisulphite to obtain pure Vilazodone, in effect, free of impurity of formula (5) as illustrated in example-4.
- an amide solvent which is preferably dimethylformamide ( DMF) before treatment with aqueous sodium metabisulphite to obtain pure Vilazodone, in effect, free of impurity of formula (5) as illustrated in example-4.
- the invention is directed towards isolated Vilazodone impurity, 5-(4-((3- (4-(4-(2-carbamoylbenzofuran-5-yl) piperazin-l-yl) butyl)-5-cyano-lH-indol-l-yl) methyl) piperazin-l-yl) benzofuran-2-carboxamide of formula (5).
- the isolated compound (5) of the present invention is used as reference marker and/or standard while testing the purity of Vilazodone and its pharmaceutically acceptable salt.
- a reference marker/standard is used for qualitative analysis and is also used to quantify the amount of the compound of the reference standard in an unknown mixture.
- the term "isolated” refers to a compound that is at least 80%, preferably at least 90%, even more preferably at least 93% pure measured as area percentage by HPLC.
- the formation of impurity of formula (5) in Vilazodone can be controlled within regulatory limits by purifying the commercially obtained raw material 5-(piperaziny-l-yl)-l-benzofuran-2-carboxamide (PBA) compound of formula (2) by acid-base treatment in water, as per example-5.
- the compound of formula (2) used for preparation of Vilazodone and its pharmaceutically acceptable salt has formaldehyde content not more than 500ppm (parts per million), more preferably not more than 300 ppm , most preferably not more than lOOppm.
- the impurity of formula (5) in crude Vilazodone is removed by treating a solution of crude Vilazodone with IPA-HCl, collecting the precipitated solid, treating the collected solid with dimethylformamide and liquor ammonia to obtain a solution which is further treated with aqueous sodium metabisulphite and sodium carbonate as illustrated in example-4.
- Pure Vilazodone obtained by the process of the present invention is further converted to its pharmaceutically acceptable salts by the processes known in the art.
- substantially pure Vilazodone hydrochloride is obtained by treating pure Vilazodone with IPA-HCl at 60-70°C, cooling the reaction mass to room temperature and then collecting the desired substantially pure Vilazodone Hydrochloride by filtration.
- IPA-HCl refers to solution of hydrochloride gas in isopropanol.
- Purity obtained of the purified Vilazodone using the process of the present invention is >99% by HPLC and that of substantially pure Vilazodone hydrochloride is >99% by HPLC.
- Vilazodone base and Vilazodone hydrochloride prepared according to the processes of the present invention can be substantially pure having purity greater than about 99% or greater than about 99.5% , or greater than about 99.7% or greater than about 99.9% as determined using high performance liquid chromatography (HPLC).
- Vilazodone base and Vilazodone hydrochloride produced by a method of present invention can be substantially pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC.
- Vilazodone base and Vilazodone hydrochloride produced by the methods of present invention can be substantially pure having purity in amounts greater than about 99.8% and containing no single impurity in amounts greater than about 0.1% by HPLC.
- crude Vilazodone and/or crude Vilazodone base refers to solid obtained after condensation of compound (2) and (3) which is subjected to a purification process.
- Vilazodone and/or Vilazodone base and/or pure Vilazodone and/or pure Vilazodone base refers to substantially pure compound of formula (1).
- Vilazodone hydrochloride refers to hydrochloride salt of compound of formula (1).
- a compound is substantially pure if it comprises less than 0.2 %, preferably less than 0.15%, more preferably less than 0.1 % or most preferably less than 0.05% of impurity of formula (4) & (5) measured as area percentage by HPLC.
- the compound (5) of the invention has utility as a reference marker for Vilazodone and Vilazodone hydrochloride because it is a potential contaminant arising from side reactions which occur during the synthesis of the drug substance.
- the test sample of drug substance to be analyzed is assayed by one or more conventional analytical techniques.
- the analytical technique includes high performance liquid chromatography (HPLC) which is used for detection and quantification of impurities in a principal compound such as the drug substance. Detection and especially quantification of components of a mixture can be accomplished with the use of response factors.
- HPLC high performance liquid chromatography
- the response of a detector in HPLC e.g. UV detectors or refractive index detectors
- Response factors as known, account for this difference in the response signal of the detector to different compounds eluting from the column.
- Analytical Methods Vilazodone Hydrochloride impurities may be determined using HPLC with the following chromatographic conditions
- Mobile phase-B Homogenous mixture of Buffer-B (aqueous ammonium acetate; 4.62 gm in 350ml HPLC grade water) and acetonitrile (35:65). Adjust pH of the mixture to 8.9 ⁇ 0.05 with ammonia. Mix well and sonicate to degas.
- Buffer-B aqueous ammonium acetate; 4.62 gm in 350ml HPLC grade water
- acetonitrile 35:65. Adjust pH of the mixture to 8.9 ⁇ 0.05 with ammonia. Mix well and sonicate to degas.
- Typical retention times that may be obtained are as follows:
- the reaction mass was heated to reflux (75-85 °C) and maintained for about 12 hrs (CBCI content is NMT 5.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) and the wet solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (500ml) and filtered through celite to remove insoluble. To the filtrated was added IPA.HC1 and the reaction mass was stirred for 60-90 min. The precipitated solid was collected by filtration, washed with DMF suck dried well.
- the wet cake was taken in a RBF and to it was added dimethylformamide. Thereafter liquor ammonia was added till pH 8.0-10.0 is obtained, the reaction mass was stirred for 30-45 min. and filtered through celite. To the filtrate was gradually added an aq. solution of sodium metabisulphite (15gm) and sodium carbonate (15 gm) in 400ml water in 45-60 min. The reaction mass was stirred for 60-90 min. the precipitated solid was collected by filtration and slurried with water, suck dried followed by slurry wash with acetone. The wet solid obtained after filtration was dried under vacuum to yield pure Vilazodone base.
- DMF 600ml
- lOOgm Vilazodone Hydrochloride
- reaction mass was then heated to reflux (75-85deg) and maintained for about 12 hrs (till CBCI content NMT 2.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water (500ml) and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) for 30-45min. The solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (700ml) and filtered through celite to remove insoluble. The celite bed was washed with DMF (lOOml).The DMF filtrate and washings were combined and preserved.
- MASS Spectra is recorded by dissolving sample in methanol using Xevo G2 QT of mass spectrometer m/z amu (atomic mass unit) Assignment
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Abstract
Cette invention concerne un procédé de préparation d'un chlorhydrate de vilazodone sensiblement pur et concerne également une impureté isolée de la vilazodone. Ledit procédé de production de vilazodone, 1-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carbonyl-benzofuran-5-yl) pipérazine représentée par la formule (1) ou d'un sel pharmaceutiquement acceptable de celle-ci comprend la condensation du composé de formule (2) avec un composé de formule (3) dans un solvant de type alcool pour obtenir un solide blanc à jaune ; l'isolement du solide obtenu ; le lavage en suspension épaisse du solide obtenu avec un solvant miscible à l'eau ; la dissolution du solide obtenu dans un solvant de type amide pour obtenir une solution ; l'ajout d'une solution aqueuse de métabisulfite de sodium et d'une base inorganique à la solution obtenue pour obtenir le composé de formule (1) et éventuellement la conversion du solide ainsi obtenu en son sel pharmaceutiquement acceptable.
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IN2001/MUM/2013 | 2013-06-12 | ||
IN2001MU2013 IN2013MU02001A (fr) | 2013-06-12 | 2014-06-11 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5532241A (en) | 1993-09-30 | 1996-07-02 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Piperidines and piperazines |
US5723614A (en) | 1995-04-20 | 1998-03-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Benzofurans |
US7799916B2 (en) | 2005-04-26 | 2010-09-21 | Merck Patent Gmbh | Process for the preparation of 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide |
US7834020B2 (en) | 2001-06-19 | 2010-11-16 | Merck Patent Gesellschaft | Polymorphic forms of 1-′4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl) piperazine hydrochloride |
WO2014061000A1 (fr) * | 2012-10-19 | 2014-04-24 | Ranbaxy Laboratories Limited | Procédé pour la préparation de vilazodone ou d'un sel pharmaceutiquement acceptable de celle-ci |
-
2014
- 2014-06-11 IN IN2001MU2013 patent/IN2013MU02001A/en unknown
- 2014-06-11 WO PCT/IB2014/062132 patent/WO2014199313A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US5532241A (en) | 1993-09-30 | 1996-07-02 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Piperidines and piperazines |
US5723614A (en) | 1995-04-20 | 1998-03-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Benzofurans |
US7834020B2 (en) | 2001-06-19 | 2010-11-16 | Merck Patent Gesellschaft | Polymorphic forms of 1-′4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl) piperazine hydrochloride |
US7799916B2 (en) | 2005-04-26 | 2010-09-21 | Merck Patent Gmbh | Process for the preparation of 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide |
WO2014061000A1 (fr) * | 2012-10-19 | 2014-04-24 | Ranbaxy Laboratories Limited | Procédé pour la préparation de vilazodone ou d'un sel pharmaceutiquement acceptable de celle-ci |
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BIN HU ET AL: "Scale-Up Synthesis of Antidepressant Drug Vilazodone", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 16, no. 9, 21 September 2012 (2012-09-21), pages 1552 - 1557, XP055061951, ISSN: 1083-6160, DOI: 10.1021/op300171m * |
SORBERA L A ET AL: "VILAZODONE HYDROCHLORIDE", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 26, no. 3, 1 January 2001 (2001-01-01), pages 247 - 252, XP009035003, ISSN: 0377-8282, DOI: 10.1358/DOF.2001.026.03.611242 * |
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