EP2121663A2 - An improved process for the preparation of rizatriptan - Google Patents
An improved process for the preparation of rizatriptanInfo
- Publication number
- EP2121663A2 EP2121663A2 EP07859030A EP07859030A EP2121663A2 EP 2121663 A2 EP2121663 A2 EP 2121663A2 EP 07859030 A EP07859030 A EP 07859030A EP 07859030 A EP07859030 A EP 07859030A EP 2121663 A2 EP2121663 A2 EP 2121663A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- formula
- rizatriptan
- compound
- formula iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229960000425 rizatriptan Drugs 0.000 title claims description 43
- 238000000034 method Methods 0.000 title claims description 36
- 238000002360 preparation method Methods 0.000 title claims description 15
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 title claims 2
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 30
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 235000010265 sodium sulphite Nutrition 0.000 claims description 10
- IOMZCWUHFGMSEJ-UHFFFAOYSA-N 4-(azaniumylamino)benzenesulfonate Chemical compound NNC1=CC=C(S(O)(=O)=O)C=C1 IOMZCWUHFGMSEJ-UHFFFAOYSA-N 0.000 claims description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 claims description 2
- 235000019252 potassium sulphite Nutrition 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 229910006069 SO3H Inorganic materials 0.000 claims 1
- ULFRLSNUDGIQQP-UHFFFAOYSA-N rizatriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CN1C=NC=N1 ULFRLSNUDGIQQP-UHFFFAOYSA-N 0.000 abstract description 44
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- JPRXYLQNJJVCMZ-UHFFFAOYSA-N Rizatriptan benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1.C1=C2C(CC[NH+](C)C)=CNC2=CC=C1CN1C=NC=N1 JPRXYLQNJJVCMZ-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- 229960004789 rizatriptan benzoate Drugs 0.000 description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000012535 impurity Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- -1 SnCl2 dihydrate Chemical class 0.000 description 8
- 239000000539 dimer Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 150000001989 diazonium salts Chemical class 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 5
- 238000006783 Fischer indole synthesis reaction Methods 0.000 description 5
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 5
- 239000012954 diazonium Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QKXMWBLNSPNBEY-UHFFFAOYSA-N 4,4-diethoxy-n,n-dimethylbutan-1-amine Chemical compound CCOC(OCC)CCCN(C)C QKXMWBLNSPNBEY-UHFFFAOYSA-N 0.000 description 4
- 229930195212 Fischerindole Natural products 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WDZKKBDOGYBYBG-UHFFFAOYSA-N 4,4-dimethoxy-n,n-dimethylbutan-1-amine Chemical compound COC(OC)CCCN(C)C WDZKKBDOGYBYBG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AYRFNHASXHCJRE-UHFFFAOYSA-N 4,4-bis[3-[2-(dimethylamino)ethyl]-5-(1,2,4-triazol-1-ylmethyl)-1h-indol-2-yl]-n,n-dimethylbutan-1-amine Chemical compound N1C2=CC=C(CN3N=CN=C3)C=C2C(CCN(C)C)=C1C(CCCN(C)C)C(=C(C1=C2)CCN(C)C)NC1=CC=C2CN1C=NC=N1 AYRFNHASXHCJRE-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical class [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical group [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 229940124433 antimigraine drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000000386 donor Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical class CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940103177 maxalt Drugs 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910001379 sodium hypophosphite Inorganic materials 0.000 description 1
- MDUSUFIKBUMDTJ-UHFFFAOYSA-N sodium;1h-1,2,4-triazole Chemical compound [Na].C=1N=CNN=1 MDUSUFIKBUMDTJ-UHFFFAOYSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- the present invention relates to an improved process for preparing N,N-dimethyl-5-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 H-indole-3-ethanamine of Formula I
- Rizatriptan benzoate is chemically known as, N,N-dimethyl-5-(lH-l,2,4-triazol-l- ylmethyl)-l H-indole-3-ethanamine monobenzoate of Formula I, which is used as an antimigraine drug.
- Rizatriptan benzoate is being marketed under the proprietary name MAXALT as an oral tablet.
- Rizatriptan is an orally active serotonin 5-HT(I) receptor agonist that potently and selectively binds to 5-HT(lB/lD) subtypes.
- Rizatriptan is used in the treatment of migrane and associated conditions like cluster headache, chronic paroxysmal hemicrains, headache associated with vascular disorders, tension headache and pediatric migrane.
- US 5,298,520 discloses a method of preparing rizatriptan comprising reacting 4- nitrobenzylbromide with 1,2,4-triazole sodium salt in anhydrous dimethylformamide to yield l-(4-nitrophenyl)methyl- 1,2,4-triazole.
- This l-(4-nitrophenyl)methyl- 1,2,4- triazole was hydrogenated using 10% PaVC in ethanol and hydrochloric acid to give l-(4-aminophenyl)niethyl- 1,2,4-triazole.
- the main disadvantage of this process is generation of large quantity of isomeric Rizatriptan due to 4-substituted triazole.
- the above process has another disadvantage of reduction of diazonium salt with SnCl 2 dihydrate in concentrated hydrochloric acid. Tin salts are notoriously toxic giving rise to significant disposal problems, and the replacement of SnCl 2 dihydrate by sodium sulphite is therefore plainly beneficial from the environmental viewpoint, especially when the process is adapted for full-scale manufacture.
- tin salts are persistent, and trace amounts thereof is frequently observed to be carried through to the final stages of the synthetic sequence unless rigorous chromatographic purification is under taken.
- This l-(4-nitrophenyl)methyl- 1,2,4- triazole was subsequently hydrogenated using transfer hydrogenation in the presence of hydrogen donor to give l-(4-aminophenyl)methyl-l,2,4-triazole and then treated with nitrous acid and then with alkali metal sulphite followed by acidification to give l-(4-hydrazinophenyl)methyl-l,2,4-triazole and insitu condensed with 4- (dimethylamino)butanal dimethylacetal to yield rizatriptan.
- the process is as summarized below:
- Hydrogenation catalyst is palladium on carbon- and hydrogenation donor is ammonium formate, sodium hypophosphite, triethylammonium formate or potassium formate.
- the disadvantage of the above process is that heating the reaction mass of hydrazine compound with acetal derivative at 90 0 C, results in the formation of rizatriptan dimeric impurities. Further, the residue of rizatriptan base is subjected to column chromatography to give pure Rizatriptan base. The process is not feasible on industrial scale operations.
- WO 2006/0531 16 A2 discloses a process to prepare Rizatriptan.
- the process comprises; condensation of l-(4-hydrazinophenyl)methyl-l,2,4-triazole dihydrochloride with 4-(dimethylamino)butanal dimethylacetal in the presence of hydrochloric acid yielded crude rizatriptan.
- This crude rizatriptan was passed through silica gel to give pure Rizatriptan that was further converted to benzoate salt of rizatriptan.
- the process is as shown below:
- Rizatriptan benzoate product is substantially free of Rizatriptan dimeric impurities such as Rizatriptan- 1,2-dimer Rizatriptan 2,2-dimer and Rizatriptan 2,5-dimer represented by the following formulae :
- the objective of the present invention is to develop a new improved process for the preparation of Rizatriptan and its pharmaceutically acceptable salts without requiring laborious purification to remove oligomeric/dimeric impurities that in turn can be used as Active Pharmaceutical Ingredient.
- the objective of the present invention is to provide an improved process for preparing Rizatriptan.
- In yet another objective of the present invention is to provide an improved process for the preparation of substantially pure Rizatriptan benzoate, which is simple, industrially applicable and economically viable.
- the present invention relates to an improved process for preparation of N, N- dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3-ethanarnine of Formula I
- Formula I and its pharmaceutically acceptable salts which comprises: a) reacting 4-(lH-(l,2,4-triazole-l-ylmethyl)benzamine of Formula II, Formula II with sodium nitrite in the presence of an acid and alkali metal sulphite to give 4- (lH-(l,2,4-triazole-l-ylmethyl)phenylhydrazinesulfonic acid of Formula III,
- the present invention relates to an improved process for the preparation of Rizatriptan followed by further conversion to Rizatriptan benzoate in moderately high yield and better quality.
- the conversion of compound Formula II to compound Formula III is achieved by converting compound II into corresponding diazonium salt using nitrous acid that on further reaction with alkali metal sulfite in presence of acid like hydrochloride and sulfuric acid afforded compound of Formula III.
- the compound of Formula III is a stable addition product and is isolated in good yield.
- the alkali metal sulfite employed suitably is selected from sodium sulfite or potassium sulfite more preferably sodium sulfite.
- Formula II is first converted to corresponding diazonium salt which on further reduction with sodium sulfite yielded the benzyltriazolehydrazine (compound 5) and this hydrazine product is isolated as dihydrochloride salt in poor yield.
- the compound of Formula III is a novel compound and forms an aspect of the present invention.
- the Fischer-Indole synthesis for the preparation of Rizatriptan of Formula I comprising condensation of compound of Formula HI with compound of Formula IV can be efficiently carried out in the presence of acid selected from hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, /7-toluenesulfonic acid, methane sulfonic acid, more preferably sulfuric acid at a temperature of about 35-45°C for 9 hrs.
- acid selected from hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, /7-toluenesulfonic acid, methane sulfonic acid, more preferably sulfuric acid at a temperature of about 35-45°C for 9 hrs.
- the reaction mixture was cooled to 0-5°C and pH adjusted to 10.5-11.0 using aqueous sodium hydroxide.
- the inventors were able to achieve the formation of Rizatriptan from Fischer-Indole reaction of benzyltriazolehydrazinesulfonic acid of Formula III with 4- (dimethylamino)butanal diethyl acetal of Formula IV, the inventors have further established that the present invention does not proceed as assumed from the prior art reaction route in which, first compound of Formula III is hydrolyzed to yield the intermediate, benzyltriazolehydrazine (compound 5) and thereafter the benzyltriazolehydrazine undergoes Fischer-Indole cyclization with Formula IV to yield rizatriptan. Rather the benzenetriazolesulfonic acid of Formula HI reacts directly with 4-(dimethylamino)butanal diethyl acetal to undergo Fischer-Indole cyclization to afford Rizatriptan.
- Fischer-Indole cyclization of compound of Formula III with compound of Formula IV could proceed at lower temperature in the range of 30-60 0 C, more particularly 35-45 °C which is contrary to the prior art procedures wherein Fischer-Indole reaction leading to Rizatriptan was carried out at higher temperature i.e >90°C.
- acid catalyzed oligomerization/dimerization of Rizatriptan could occur when the reaction was done at higher temperature. Since the Fischer-Indole reaction of compound of Formula III with compound of Formula IV was carried out at lower temperature, the formation of dimeric impurities was advantageously controlled in this process.
- the present invention furnishes Rizatriptan that contains no greater than 0.5 % of all dimers as determined by high performance chromatography (HPLC).
- the Fischer-Indole cyclization of compound of Formula III with compound of Formula IV to prepare Rizatriptan is normally associated with the formation of large amounts of the oligomeric/dimeric impurities Viz Rizatriptan-2,5-dimer, Rizatriptan 2,2-dimer and Rizatriptan- 1,2 dimer that are difficult to remove.
- the inventors were able to modify the reaction conditions so as to reduce the formation of the dimer impurities to the acceptable regulatory limits. Also in the process of the present invention, the formation of the dimer impurities was reduced by carrying out the reaction with the compound of Formula III.
- Rizatriptan benzoate appears as an oily mass and hence difficult to crystallize.
- Rizatriptan benzoate is obtained as a solid without chromatographic purification.
- the obtained Rizatriptan benzoate salt is purified by crystallizing in ethanol.
- the condensation of the sulfonic acid of compound of Formula III with compound of Formula IV leading to the formation of rizatriptan base proceeds very fast when compared with the condensation of simple benzyltriazolehydrazine (compound 5) under similar reaction conditions thus imparting high throughput capability to the process.
- the compound of Formula II is prepared by known methods in the literature.
- the compound of Formula I is further converted to rizatriptan benzoate involving the reaction of free base with benzoic acid in a suitable solvent, optionally followed by purification of benzoate salt.
- suitable solvents that can be used for the preparation of solution of benzoic acid include, without limitation, acetone, ethanol, isopropanol, n- propanol and n-butanol.
- Acetone has been found to be an excellent choice for the preparation of benzoate salt.
- another advantage with acetone is that the oligomeric impurities could almost be eliminated in the acetone filtrate during the isolation of the rizatriptan benzoate product.
- Suitable solvents for recrystallization of the crude benzoate salt include, without limitation, acetone, ethanol, isopropanol, n-propanol and n-butanol.
- the Rizatriptan base was dissolved in acetone (200 ml) and stirred with benzoic acid (22.69 g, 0.186 mol) at 0-5 0 C for 3 h.
- the solid precipitated was filtered and stirred in a mixture of ethanol (50 ml) and acetone (25 ml) at 60-65 0 C for 1 h.
- the resulting slurry was cooled to 5-1O 0 C and filtered to obtain crude Rizatriptan benzoate product.
- This crude Rizatriptan benzoate was crystallized from ethanol to obtain pure Rizatriptan benzoate.
- YIELD 16 g (HPLC PURITY: >99.6%)
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Abstract
The present invention relates to an improved process for preparing N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine of Formula (I) and its pharmaceutically acceptable salts.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF RIZATRIPTAN
FIELD OF THE INVENTION
The present invention relates to an improved process for preparing N,N-dimethyl-5-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 H-indole-3-ethanamine of Formula I
Formula I
and its pharmaceutically acceptable salts. BACKGROUND OF THE INVENTION
Rizatriptan benzoate is chemically known as, N,N-dimethyl-5-(lH-l,2,4-triazol-l- ylmethyl)-l H-indole-3-ethanamine monobenzoate of Formula I, which is used as an antimigraine drug. Rizatriptan benzoate is being marketed under the proprietary name MAXALT as an oral tablet.
Rizatriptan is an orally active serotonin 5-HT(I) receptor agonist that potently and selectively binds to 5-HT(lB/lD) subtypes. Rizatriptan is used in the treatment of migrane and associated conditions like cluster headache, chronic paroxysmal hemicrains, headache associated with vascular disorders, tension headache and pediatric migrane.
US 5,298,520 discloses a method of preparing rizatriptan comprising reacting 4- nitrobenzylbromide with 1,2,4-triazole sodium salt in anhydrous dimethylformamide to yield l-(4-nitrophenyl)methyl- 1,2,4-triazole. This l-(4-nitrophenyl)methyl- 1,2,4- triazole was hydrogenated using 10% PaVC in ethanol and hydrochloric acid to give l-(4-aminophenyl)niethyl- 1,2,4-triazole. Subsequently the l-(4-aminophenyl)methyl- 1,2,4-triazole was treated with sodium nitrite in the presence of concentrated
hydrochloric acid and SnCl2 dihydrate to give l-(4-hydrazinophenyl)methyl- 1,2,4- triazole dihydrochloride, which on further condensation with 4- (dimethylamino)butanal dimethylacetal in aqueous sulphuric acid yielded Rizatriptan. Rizatriptan base was converted to its benzoate salt using benzoic acid in diethyl ether. The process is as summarized below:
Benzoic acid in diethyl ether
The main disadvantage of this process is generation of large quantity of isomeric Rizatriptan due to 4-substituted triazole. Further, the above process has another disadvantage of reduction of diazonium salt with SnCl2 dihydrate in concentrated hydrochloric acid. Tin salts are notoriously toxic giving rise to significant disposal problems, and the replacement of SnCl2 dihydrate by sodium sulphite is therefore plainly beneficial from the environmental viewpoint, especially when the process is adapted for full-scale manufacture. Moreover, tin salts are persistent, and trace
amounts thereof is frequently observed to be carried through to the final stages of the synthetic sequence unless rigorous chromatographic purification is under taken.
US 5,567,819 claims a process to prepare Rizatriptan, by reacting 4-nitrobenzylhalide with 4-amino-l,2,4-triazole to yield 4-amino-l-(4-nitrophenyl)methyl- 1,2,4- triazolium halide which was further deaminated in the presence of nitrous acid to yield l-(4-nitrophenyl)methyl-l,2,4-triazole. This l-(4-nitrophenyl)methyl- 1,2,4- triazole was subsequently hydrogenated using transfer hydrogenation in the presence of hydrogen donor to give l-(4-aminophenyl)methyl-l,2,4-triazole and then treated with nitrous acid and then with alkali metal sulphite followed by acidification to give l-(4-hydrazinophenyl)methyl-l,2,4-triazole and insitu condensed with 4- (dimethylamino)butanal dimethylacetal to yield rizatriptan. The process is as summarized below:
enation
wherein D represents a halogen atom. Hydrogenation catalyst is palladium on carbon- and hydrogenation donor is ammonium formate, sodium hypophosphite, triethylammonium formate or potassium formate. The disadvantage of the above
process is that heating the reaction mass of hydrazine compound with acetal derivative at 900C, results in the formation of rizatriptan dimeric impurities. Further, the residue of rizatriptan base is subjected to column chromatography to give pure Rizatriptan base. The process is not feasible on industrial scale operations.
WO 2006/0531 16 A2 discloses a process to prepare Rizatriptan. The process comprises; condensation of l-(4-hydrazinophenyl)methyl-l,2,4-triazole dihydrochloride with 4-(dimethylamino)butanal dimethylacetal in the presence of hydrochloric acid yielded crude rizatriptan. This crude rizatriptan was passed through silica gel to give pure Rizatriptan that was further converted to benzoate salt of rizatriptan. The process is as shown below:
The disadvantage of the above process is use of silica gel column to purify the rizatriptan base. Hence, the process will not be economical.
We have now found an improved process to prepare Rizatriptan, which is industrially feasible, with good yields and good quality. Further, the Rizatriptan benzoate product is substantially free of Rizatriptan dimeric impurities such as Rizatriptan- 1,2-dimer Rizatriptan 2,2-dimer and Rizatriptan 2,5-dimer represented by the following formulae :
OBJECTIVE
The objective of the present invention is to develop a new improved process for the preparation of Rizatriptan and its pharmaceutically acceptable salts without requiring laborious purification to remove oligomeric/dimeric impurities that in turn can be used as Active Pharmaceutical Ingredient.
The objective of the present invention is to provide an improved process for preparing Rizatriptan.
In yet another objective of the present invention is to provide an improved process for the preparation of substantially pure Rizatriptan benzoate, which is simple, industrially applicable and economically viable.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparation of N, N- dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3-ethanarnine of Formula I
Formula I
and its pharmaceutically acceptable salts which comprises: a) reacting 4-(lH-(l,2,4-triazole-l-ylmethyl)benzamine of Formula II,
Formula II with sodium nitrite in the presence of an acid and alkali metal sulphite to give 4- (lH-(l,2,4-triazole-l-ylmethyl)phenylhydrazinesulfonic acid of Formula III,
Formula III
b) isolating the 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazine sulfonic acid of Formula III and c) cyclizing with a compound of Formula IV
Formula IV
wherein Ri and R2 are independently Ci-4 alkyl
in the presence of acid to give rizatriptan of Formula I followed by conversion to its pharmaceutically acceptable salts.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Rizatriptan followed by further conversion to Rizatriptan benzoate in moderately high yield and better quality.
The conversion of compound Formula II to compound Formula III is achieved by converting compound II into corresponding diazonium salt using nitrous acid that on further reaction with alkali metal sulfite in presence of acid like hydrochloride and sulfuric acid afforded compound of Formula III. The compound of Formula III is a stable addition product and is isolated in good yield. The alkali metal sulfite employed suitably is selected from sodium sulfite or potassium sulfite more preferably sodium sulfite. In the prior art, Formula II is first converted to corresponding diazonium salt which on further reduction with sodium sulfite yielded the benzyltriazolehydrazine (compound 5) and this hydrazine product is isolated as dihydrochloride salt in poor yield. In general, the reduction of diazonium compound with sodium sulfite could proceed through a sodium sulfite addition intermediate complex which on in-situ digestion in acidic medium yields the hydrazine product and this intermediate sulfite addition product could not be isolated from the reaction mass. Instead the inventors surprisingly isolated addition product of Formula III as a stable compound. Further it was observed that it could be advantageous to isolate the compound Formula III. This compound III could be easily crystallized from the reaction mass and purified by acid base treatment.
The compound of Formula III is a novel compound and forms an aspect of the present invention.
The Fischer-Indole synthesis for the preparation of Rizatriptan of Formula I comprising condensation of compound of Formula HI with compound of Formula IV can be efficiently carried out in the presence of acid selected from hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, /7-toluenesulfonic acid, methane sulfonic acid, more preferably sulfuric acid at a temperature of about 35-45°C for 9 hrs. Upon completion, the reaction mixture was cooled to 0-5°C and pH adjusted to 10.5-11.0 using aqueous sodium hydroxide. The product was extracted with ethyl acetate and extract concentrated under reduced pressure to obtain Rizatriptan base as an oily mass. This particular temperature conditions employed in the condensation of the compound of Formula III and IV yielded pure Rizatriptan with Rizatriptan-2,5-dimer impurity less than 0.5 %. The major advantage realized by this reaction conditions set forth in this invention is the elimination of chromatography as compared to prior-art procedures wherein extensive chromatographic separation is carried out.
The inventors were able to achieve the formation of Rizatriptan from Fischer-Indole reaction of benzyltriazolehydrazinesulfonic acid of Formula III with 4- (dimethylamino)butanal diethyl acetal of Formula IV, the inventors have further established that the present invention does not proceed as assumed from the prior art reaction route in which, first compound of Formula III is hydrolyzed to yield the intermediate, benzyltriazolehydrazine (compound 5) and thereafter the benzyltriazolehydrazine undergoes Fischer-Indole cyclization with Formula IV to yield rizatriptan. Rather the benzenetriazolesulfonic acid of Formula HI reacts directly with 4-(dimethylamino)butanal diethyl acetal to undergo Fischer-Indole cyclization to afford Rizatriptan.
In another embodiment, the inventors found that Fischer-Indole cyclization of compound of Formula III with compound of Formula IV could proceed at lower temperature in the range of 30-60 0C, more particularly 35-45 °C which is contrary to the prior art procedures wherein Fischer-Indole reaction leading to Rizatriptan was
carried out at higher temperature i.e >90°C. During the Fischer-Indole synthesis, acid catalyzed oligomerization/dimerization of Rizatriptan could occur when the reaction was done at higher temperature. Since the Fischer-Indole reaction of compound of Formula III with compound of Formula IV was carried out at lower temperature, the formation of dimeric impurities was advantageously controlled in this process.
More specifically, the present invention furnishes Rizatriptan that contains no greater than 0.5 % of all dimers as determined by high performance chromatography (HPLC).
The Fischer-Indole cyclization of compound of Formula III with compound of Formula IV to prepare Rizatriptan is normally associated with the formation of large amounts of the oligomeric/dimeric impurities Viz Rizatriptan-2,5-dimer, Rizatriptan 2,2-dimer and Rizatriptan- 1,2 dimer that are difficult to remove. The inventors were able to modify the reaction conditions so as to reduce the formation of the dimer impurities to the acceptable regulatory limits. Also in the process of the present invention, the formation of the dimer impurities was reduced by carrying out the reaction with the compound of Formula III. Since it was found that in earlier published procedures benzyltriazolehydrazine intermediate (compound 5) when condensed with compound of Formula IV produced rizatriptan in very low yield coupled with large amounts of the above mentioned dimeric/oligomeric impurities.
Also, the prior-art process containing high amounts of oligomers and polymers makes the Rizatriptan benzoate appear as an oily mass and hence difficult to crystallize. However, with the present process of the invention, it is noteworthy to mention that Rizatriptan benzoate is obtained as a solid without chromatographic purification. The obtained Rizatriptan benzoate salt is purified by crystallizing in ethanol.
Also the condensation of the sulfonic acid of compound of Formula III with compound of Formula IV leading to the formation of rizatriptan base proceeds very fast when compared with the condensation of simple benzyltriazolehydrazine (compound 5) under similar reaction conditions thus imparting high throughput capability to the process.
The compound of Formula II is prepared by known methods in the literature.
The compound of Formula I is further converted to rizatriptan benzoate involving the reaction of free base with benzoic acid in a suitable solvent, optionally followed by purification of benzoate salt. Suitable solvents that can be used for the preparation of solution of benzoic acid include, without limitation, acetone, ethanol, isopropanol, n- propanol and n-butanol. Acetone has been found to be an excellent choice for the preparation of benzoate salt. Also another advantage with acetone is that the oligomeric impurities could almost be eliminated in the acetone filtrate during the isolation of the rizatriptan benzoate product.
Suitable solvents for recrystallization of the crude benzoate salt include, without limitation, acetone, ethanol, isopropanol, n-propanol and n-butanol.
The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
Example 1
Preparation of 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazinesulfonic acid
A solution of 4-(lH-l,2,4-triazol-ϊ-ylmethyl)benzenamine (50 g, 0.287 mol) in aqueous hydrochloric acid (-17% w/w, 300 ml) was cooled to -5 to -1O0C. To this chilled solution, a solution of sodium nitrite (25.74 g, 0.373 mol) in water (50 ml) was added slowly at -5 to -1O0C to obtain a solution of diazonium salt. In a separate flask,
sodium sulfite (90.40 g, 0.717 mol) was taken in water (300 ml) and cooled to 0-50C. To this sodium sulfite solution, above diazonium salt solution was added rapidly at 0-5° C and continued to stir the reaction mixture at 0-5° C for 30 min. Thereafter, the temperature of the reaction mixture was raised to 25-3O0C and continued to stir at 25- 3O0C for 2 h to allow the title product to crystallize out. The isolated solid was filtered and dissolved in water (250 ml) by adjusting the pH to 6.5-7.0 using aqueous ammonia. Thereafter, the aqueous solution was washed with methylene chloride and the aqueous layer pH was readjusted to 2.0-2.2 to isolate the product. The product was filtered and dried at 45-500C under reduced pressure to constant weight. YIELD: 56 g
Example 2
Preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indoIe-3- ethanamine benzoate
A mixture of 4-(lH-l,2,4-triazol-lylmethyl)phenylhydrazinesulfonic acid (50 g, 0.186 mol) and 4-(dimethylamino)butanal diethyl acetal (45.70 g, 0.242 mol) was stirred in 15 % w/w aqueous sulfuric acid (500 ml) at 35-4O0C for 9 h. The reaction mixture was then cooled to 0-50C and pH was adjusted to 10.5-11.0 using aqueous sodium hydroxide solution. The product was extracted with ethyl acetate and the solvent was removed by distillation under reduced pressure to obtain the Rizatriptan base as an oily mass. The Rizatriptan base was dissolved in acetone (200 ml) and stirred with benzoic acid (22.69 g, 0.186 mol) at 0-50C for 3 h. The solid precipitated was filtered and stirred in a mixture of ethanol (50 ml) and acetone (25 ml) at 60-650C for 1 h. The resulting slurry was cooled to 5-1O0C and filtered to obtain crude Rizatriptan benzoate product. This crude Rizatriptan benzoate was crystallized from ethanol to obtain pure Rizatriptan benzoate. YIELD: 16 g (HPLC PURITY: >99.6%)
Example 3
Preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3- ethanamine benzoate
A mixture of 4-(lH-l,2,4-triazol-lylmethyl)phenylhydrazinesulfonic acid (50 g, 0.186 mol) and 4-(dimethylamino)butanal diethyl acetal (45.70 g, 0.242 mol) was stirred in 15 % w/w aqueous sulfuric acid (500 ml) at 38-420C for 9 h. The reaction mixture was then cooled to 0-50C and pH was adjusted to 10.5-11.0 using aqueous sodium hydroxide solution. The product was extracted with ethyl acetate and the solvent was removed by distillation under reduced pressure to obtain the Rizatriptan base as an oily mass. The Rizatriptan base was dissolved in acetone (200 ml) and stirred with benzoic acid (22.69 g, 0.186 mol) at 0-50C for 3 h. The solid precipitated was filtered and stirred in a mixture of ethanol (50 ml) and acetone (25 ml) at 60-650C for 1 h. The resulting slurry was cooled to 5-1O0C and filtered to obtain crude Rizatriptan benzoate product. This crude Rizatriptan benzoate was crystallized from ethanol to obtain pure Rizatriptan benzoate. YIELD: 16 g (HPLC PURITY: >99.6%)
Claims
1. An improved process for the preparation of N,N-dimethyl-5-(lH-l,2,4-triazol-l- ylmethyl)-lH-indole-3-ethanamine of Formula I
Formula I and its pharmaceutically acceptable salts which comprises : a) reacting a compound of Formula III
Formula III with a compound of Formula IV Formula IV wherein Ri and R2 are independently C1-4 alkyl in the presence of an acid to give compound of Formula I.
2. The process according to claim 1, wherein the acid used is selected from hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, formic acid, p- toluenesulfonic acid, methanesulfonic acid, more preferably sulfuric acid.
3. A process for the preparation of 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazine sulfonic acid of compound of Formula III
Formula III which comprises : a) reacting 4-( 1 H-( 1 ,2,4-triazole- 1 -ylmethyl)benzamine of Formula II, Formula II with sodium nitrite in the presence of an acid and alkali metal sulphite to give 4-(lH-(l,2,4-triazole-l-ylmethyl)phenylhydrazinesulfonic acid of Formula HI, b) isolating the 4-(lH-l,2,4-triazol-l-ylmethyl)phenylhydrazine sulfonic acid of Formula III.
4. The process according to claim 3, wherein the acid employed is selected from hydrochloric acid, sulfuric acid, more preferably hydrochloric acid.
5. The process according to claim 3, wherein the alkali metal sulphite employed is selected from sodium sulfite, potassium sulfite, more preferably sodium sulfite.
6. The process according to claim 3, wherein the reaction is conducted at below 500C.
7. The compound of Formula III NH- NH-SO3H Formula III
8. Use of compound of Formula III in the preparation of Rizatriptan of Formula I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2336CH2006 | 2006-12-15 | ||
| PCT/IB2007/003896 WO2008075163A2 (en) | 2006-12-15 | 2007-12-10 | An improved process for the preparation of rizatriptan |
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| EP2121663A2 true EP2121663A2 (en) | 2009-11-25 |
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| CN103387570A (en) * | 2013-08-20 | 2013-11-13 | 余鲜红 | Preparation method of rizatriptan benzoate |
| CN103664900B (en) * | 2013-11-25 | 2016-02-24 | 四川大学 | A kind of method preparing rizatriptan benzoate |
| CN103664901B (en) * | 2013-11-25 | 2016-04-13 | 四川大学 | A kind of rizatriptan benzoate preparation method |
| CN108892648A (en) * | 2018-07-13 | 2018-11-27 | 山东贵邦药业有限公司 | A kind of Lizakuputan benzoate intermediate process for solid phase synthesis |
| CN117362217A (en) * | 2023-10-10 | 2024-01-09 | 上海颐碳化学科技有限公司 | Method for synthesizing indole compounds |
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| WO2008075163A2 (en) | 2008-06-26 |
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