WO2007054784A1 - An improved process for the preparation of granisetron hydrochloride - Google Patents
An improved process for the preparation of granisetron hydrochloride Download PDFInfo
- Publication number
- WO2007054784A1 WO2007054784A1 PCT/IB2006/003146 IB2006003146W WO2007054784A1 WO 2007054784 A1 WO2007054784 A1 WO 2007054784A1 IB 2006003146 W IB2006003146 W IB 2006003146W WO 2007054784 A1 WO2007054784 A1 WO 2007054784A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- granisetron
- compound
- methyl
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229960003607 granisetron hydrochloride Drugs 0.000 title claims abstract description 13
- QYZRTBKYBJRGJB-UHFFFAOYSA-N hydron;1-methyl-n-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)indazole-3-carboxamide;chloride Chemical compound Cl.C1=CC=C2C(C(=O)NC3CC4CCCC(C3)N4C)=NN(C)C2=C1 QYZRTBKYBJRGJB-UHFFFAOYSA-N 0.000 title claims abstract description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims abstract description 16
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 150000007530 organic bases Chemical class 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- MFWNKCLOYSRHCJ-UHFFFAOYSA-N 1-Methyl-N-{9-methyl-9-azabicyclo[3.3.1]nonan-3-yl}-1H-indazole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)NC3CC4CCCC(C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-UHFFFAOYSA-N 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- HVHZEKKZMFRULH-UHFFFAOYSA-N 2,6-ditert-butyl-4-methylpyridine Chemical compound CC1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1 HVHZEKKZMFRULH-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- -1 alkyl chloroformate Chemical compound 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- CJKRXEBLWJVYJD-UHFFFAOYSA-N N,N'-diethylethylenediamine Chemical compound CCNCCNCC CJKRXEBLWJVYJD-UHFFFAOYSA-N 0.000 claims 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 18
- 229960003727 granisetron Drugs 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OVVDFORZEGKEJM-UHFFFAOYSA-N 1-methylindazole-3-carboxylic acid Chemical compound C1=CC=C2N(C)N=C(C(O)=O)C2=C1 OVVDFORZEGKEJM-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- YRJCXPFMFZIXRI-UHFFFAOYSA-N nonan-3-amine Chemical compound CCCCCCC(N)CC YRJCXPFMFZIXRI-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MFWNKCLOYSRHCJ-AGUYFDCRSA-N 1-methyl-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]-3-indazolecarboxamide Chemical compound C1=CC=C2C(C(=O)NC3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-AGUYFDCRSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- ISJOIAXYGBDHPF-UHFFFAOYSA-N 2-cyclononyl-1-methylazonane Chemical compound CN1CCCCCCCC1C1CCCCCCCC1 ISJOIAXYGBDHPF-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KMLTWGTWOCAQGR-UHFFFAOYSA-N CC(CC1)(C2C3)N2C1CC3NC(c1n[n](C)c2c1cccc2)=O Chemical compound CC(CC1)(C2C3)N2C1CC3NC(c1n[n](C)c2c1cccc2)=O KMLTWGTWOCAQGR-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Definitions
- the present invention relates to an improved process for the preparation of Granisetron hydrochloride of formula (I). More particularly this invention relates to the preparation of Granisetron hydrochloride using methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic base such as triethylamine.
- MIBK methyl isobutyl ketone
- Granisetron hydrochloride which is chemically known as endo-l-methyl-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)-lH-indazole-3-carboxamide monohydrochloride is a 5-HT (5 -hydroxy triptamine) antagonist, and has the following structural formula:
- Granisetron hydrochloride is useful as an anti-emetic and marketed as Kytril by Roche.
- EP-A-0200444 provides certain 5-HT (5-hydroxytryptamine) antagonists, which are described as possessing a number of therapeutic utilities, inter alia, the prevention of vomiting following the administration of cytotoxic agents.
- the compound described in Example 6 is endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)- l-methylindazole-3-carboxamide, and this compound has been assigned the INN Granisetron.
- EP-A-0200444 also discloses that Granisetron can be prepared by reacting l-methylindazole-3-carboxylic acid chloride with endo-3-amino-9-methyl-9-azabicyclo [3.3.1] nonane.
- EP 748321 claims a process for preparing Granisetron or a pharmaceutical acceptable salt thereof.
- the process comprises the condensation of compound of formula (3) and (4) followed by de-protecting the intermediate compound of structure (2) to get the granisetron or optionally forming a pharmaceutically accepted salt of Granisetron.
- Q is a leaving group displaceable by a secondary amine wherein R may be represented as benzyl, benzyl substituted with one or more chloro, alkyl or alkoxy group, t-butyl, allyl or a t-butyldimethylsilylgroup.
- Granisetron by cyclisation of a previously methylated compound of formula (C), which is shown below.
- the methylation prior to cyclisation is carried out with sodium hydride and methyl iodide as disclosed in example 1 (b) of said patent.
- the cyclisation conditions applied to that compound of formula (C) may facilitate demethylation of the indazole of the Granisetron so obtained.
- examples 2 and 3 of said patent described the cyclisation reaction, but although in example 2 the reaction leads to Granisetron, in example 3, when the reaction time is increased under the same conditions, quantitatively demethylated Granisetron is provided.
- the reaction time therefore has a consideration influence on the yield values in the second step of the process that is in the cyclisation, since the Granisetron provided by this process contains as an impurity significant amounts of demethylated Granisetron, which will have to be re-methylated in an additional step.
- MIBK methyl isobutyl ketone
- the main objective of the present invention is to provide an improved process for the preparation of compound of formula (I), which would be easy to implement on commercial scale and which can avoid the use of toxic solvents like methylene chloride, dimethylformamide, tetrahydrofuran, toluene, benzene etc.
- Another objective of the present invention is to reduce the number of steps in the preparation of compound of formula (I).
- Still another objective of the present invention is to provide a process for the preparation of compound of formula (I) in high yield and purity.
- Yet another objective of the present invention is to produce an economically viable method of preparation of compound of formula (I), thereby reducing the cost of production.
- the present invention provides an improved process for the preparation of Granisetron hydrochloride (I), comprising the steps of;
- R is Cj to C 4 alkyl.
- the reaction step is performed in a single solvent.
- the solvent is selected from the group consisting of ketonic solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl isopropyl ketone and methyl propyl ketone, the most preferred solvent is methyl isobutyl ketone (MIBK).
- MIBK methyl isobutyl ketone
- the reaction step is performed in the presence of an organic base.
- the organic base is selected from the group consisting of N,N-diethylmethylamine, N,N-diethylaniline, N 5 N- diethylethylenediamine, N,N-diisopropylethylamine, dimethylaminopyridine, triethylamine, N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4- methylpyridine, pyridine and diethylamine, the most preferred base is triethylamine.
- the reaction step is preferably performed at a temperature in the range of (-) 40° C to 30° C. Most preferred reaction temperature is in the range of (-) 5° C to 0° C.
- the purification step is performed in an alcoholic solvent, which is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof, the most preferred alcoholic solvent is methanol.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (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 Granisetron hydrochloride of formula (I). More particularly this invention relates to the preparation of Granisetron hydrochloride using methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic base such as triethylamine.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF GRANISETRON
HYDROCHLORIDE
Field of the Invention:
The present invention relates to an improved process for the preparation of Granisetron hydrochloride of formula (I). More particularly this invention relates to the preparation of Granisetron hydrochloride using methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic base such as triethylamine.
(I)
Background of the Invention:
Granisetron hydrochloride which is chemically known as endo-l-methyl-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)-lH-indazole-3-carboxamide monohydrochloride is a 5-HT (5 -hydroxy triptamine) antagonist, and has the following structural formula:
(I)
Granisetron hydrochloride is useful as an anti-emetic and marketed as Kytril by Roche.
COMHRIVIATIOM COPY
EP-A-0200444 provides certain 5-HT (5-hydroxytryptamine) antagonists, which are described as possessing a number of therapeutic utilities, inter alia, the prevention of vomiting following the administration of cytotoxic agents. The compound described in Example 6 is endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)- l-methylindazole-3-carboxamide, and this compound has been assigned the INN Granisetron. EP-A-0200444 also discloses that Granisetron can be prepared by reacting l-methylindazole-3-carboxylic acid chloride with endo-3-amino-9-methyl-9-azabicyclo [3.3.1] nonane.
EP 748321 claims a process for preparing Granisetron or a pharmaceutical acceptable salt thereof. The process comprises the condensation of compound of formula (3) and (4) followed by de-protecting the intermediate compound of structure (2) to get the granisetron or optionally forming a pharmaceutically accepted salt of Granisetron. The scheme is presented below in which Q is a leaving group displaceable by a secondary amine wherein R may be represented as benzyl, benzyl substituted with one or more chloro, alkyl or alkoxy group, t-butyl, allyl or a t-butyldimethylsilylgroup.
GRANISETRON
US Pat. No. 6,268,498 discloses an alternative process for preparing
Granisetron, by cyclisation of a previously methylated compound of formula (C), which is shown below. It should be noted that the methylation prior to cyclisation is carried out with sodium hydride and methyl iodide as disclosed in example 1 (b) of said patent. However, the cyclisation conditions applied to that compound of formula (C)
may facilitate demethylation of the indazole of the Granisetron so obtained. Thus, for example, in examples 2 and 3 of said patent described the cyclisation reaction, but although in example 2 the reaction leads to Granisetron, in example 3, when the reaction time is increased under the same conditions, quantitatively demethylated Granisetron is provided. The reaction time therefore has a consideration influence on the yield values in the second step of the process that is in the cyclisation, since the Granisetron provided by this process contains as an impurity significant amounts of demethylated Granisetron, which will have to be re-methylated in an additional step.
(C) ES 2,124,162 patent discloses a procedure for the preparation of Granisetron or its pharmaceutically acceptable salts consisting of reaction of l-methylindazole-3- carboxamide of formula (A) with 9-methyl-9-azabicyclononane of formula (B) (L = halogen, OMs, OTs; halogen = esp. Cl, Br; Ms = SO2Me; Ts = SO2C6H4Me4). Thus, l-methylindazole-3-carboxamide in tetrahydrofuran (THF) containing tetramethylethylenediamine is treated with BuLi in hexane followed by addition of endo-3-(mesyloxy)-9-methyl-9-azabicyclo [3.3.1] nonane hydrochloride (L = OMs) to give the title compound i.e. Granisetron The scheme is represented below:
(A) (B) GRANISETRON
As discussed above none of the prior art references disclosed or claimed the use of methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic
Λ
4
base such as triethylamine for the preparation of compound of formula (I), hence we focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) in substantial good yield and high purity.
Objectives of the Invention:
The main objective of the present invention is to provide an improved process for the preparation of compound of formula (I), which would be easy to implement on commercial scale and which can avoid the use of toxic solvents like methylene chloride, dimethylformamide, tetrahydrofuran, toluene, benzene etc.
Another objective of the present invention is to reduce the number of steps in the preparation of compound of formula (I).
Still another objective of the present invention is to provide a process for the preparation of compound of formula (I) in high yield and purity.
Yet another objective of the present invention is to produce an economically viable method of preparation of compound of formula (I), thereby reducing the cost of production.
Summary of the Invention:
Accordingly, the present invention provides an improved process for the preparation of Granisetron hydrochloride (I), comprising the steps of;
(I)
(a) reacting 1 -methyl indazole-3-carboxylic acid of formula (II) with alkyl chloro formate of formula (III) in the presence of an organic base and ketonic solvent to get a mixed anhydride of formula (IV);
(b) condensing the mixed anhydride of formula (IV) with compound of formula (V) to get Granisetron base of formula (VI);
(c) optionally isolating the Granisetron base of formula (VI) and purifying by using alcoholic solvent;
(d) converting the compound of formula (VI) in to compound of formula (I).
The process is shown in the scheme given below:
(D (VI)
wherein R is Cj to C4 alkyl.
Description of the Invention:
In an embodiment of the present invention, the reaction step is performed in a single solvent. The solvent is selected from the group consisting of ketonic solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl isopropyl ketone and methyl propyl ketone, the most preferred solvent is methyl isobutyl ketone (MIBK).
In another embodiment of the present invention, the reaction step is performed in the presence of an organic base. The organic base is selected from the group consisting of N,N-diethylmethylamine, N,N-diethylaniline, N5N- diethylethylenediamine, N,N-diisopropylethylamine, dimethylaminopyridine, triethylamine, N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4- methylpyridine, pyridine and diethylamine, the most preferred base is triethylamine.
In yet another embodiment of the present invention, the reaction step is preferably performed at a temperature in the range of (-) 40° C to 30° C. Most preferred reaction temperature is in the range of (-) 5° C to 0° C.
In yet another embodiment of the present invention, the purification step is performed in an alcoholic solvent, which is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof, the most preferred alcoholic solvent is methanol.
Starting materials of this invention are prepared according to the literature available in the prior art.
The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.
Example (1) Preparation of Granisetron hydrochloride
10OmL of methyl isobutyl ketone (MIBK), 8.6g of triethylamine and 1Og of 1- methyl indazole-3-carboxylic acid were placed in a 25OmL RBF. The reaction mass was stirred and treated with 7.4g of ethyl chloro formate at O0C to (-) 50C to get a mixed anhydride and then condensed with 8.75g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 100 mL of water was added, organic layer separated and distilled to 8 volumes of MIBK, cooled the reaction mass and treated with 10.3g of IPA/HC1 (~ 20%) to get 1Og of Granisetron hydrochloride.
Example (2) Preparation of Granisetron base
75OmL of methyl isobutyl ketone, 4Og of triethylamine and 5Og of 1-methyl indazole-3-carboxylic acid were placed in a 2L RBF. The reaction mass was stirred and treated with 34g of ethyl chloro formate at 20°C to 25°C to get a mixed anhydride and then condensed with 48g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 500 mL of water was added and the organic layer separated, washed with 5% sodium carbonate
(50OmL) solution and distilled the organic layer to obtain Granisetron freebase with HPLC purity 99.91%.
Example (2 - a ) Preparation of Granisetron hydrochloride
1Og of Granisetron freebase, 10OmL of methanol were placed in 250 mL RBF and heated the reaction mass to 400C to 550C to get a clear solution. The clear solution was filtered and treated with 3.5g of concentrated hydrochloric acid (36%) and diluted the reaction mass with 20OmL of MIBK, heated the reaction mass to 600C to 65°C and distilled the reaction mass up to 10 to 12 Volumes. The reaction mass was cooled and isolated 1Og of Granisetron hydrochloride with HPLC purity 99.91%.
Claims
(1) A process for the preparation of Granisetron hydrochloride of formula (I), comprising the steps of;
(a) reacting l-methylindazole-3-carboxylic acid of formula (II) with alkyl chloroformate of formula (III) in the presence of an organic base and ketonic solvent to get a mixed anhydride of formula (IV);
(b) condensing the mixed anhydride of formula (IV) with compound of formula (V) to get a Granisetron base of formula (VI);
(c) optionally isolating the Granisetron base of formula (VI) and purifying by using an alcoholic solvent; and
(d) converting the compound of formula (VI) in to compound of formula (I).
(2) A process according to claim 1, wherein R in the compound of formula (III) is Ci to C4 alkyl, preferably ethyl chloroformate.
(3) A process according to claim 1, wherein the ketonic solvent is selected from the group comprising of acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl isopropyl ketone, methyl propyl ketone and mixtures thereof, preferably methyl isobutyl ketone.
(4) A process according to claim 1, wherein the organic base is selected from the group comprising of triethylamine, N,N-diethylmethylamine, N,N-diethylaniline, N3N diethylethylenediamine, N,N-diisopropylethylamine, dimethylaminopyridine, N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine, pyridine and diethylamine, preferably triethylamine.
(5) A process according to claim 1, wherein the said reaction is performed in the temperature range of (-) 40° C to 30° C, preferably (-) 5° C to 0° C.
(6) A process according to claim 1, wherein the alcoholic solvent is selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof, preferably methanol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1643/CHE/2005 | 2005-11-10 | ||
| IN1643CH2005 | 2005-11-10 |
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| WO2007054784A1 true WO2007054784A1 (en) | 2007-05-18 |
| WO2007054784A8 WO2007054784A8 (en) | 2007-08-09 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008117282A1 (en) * | 2007-03-27 | 2008-10-02 | Chemagis Ltd. | Polymorph of granisetron base and production process therefor |
| EP2323654A1 (en) * | 2008-08-19 | 2011-05-25 | ScinoPharm Taiwan, Ltd. | Polymorphic form of granisetron hydrochloride and methods of making the same |
| CN103159765A (en) * | 2011-12-15 | 2013-06-19 | 北京嘉林药业股份有限公司 | Indisetron purification method suitable for industrialization |
| CN115372487A (en) * | 2021-05-18 | 2022-11-22 | 成都倍特药业股份有限公司 | HPLC (high Performance liquid chromatography) determination method for impurity E in granisetron hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200444A2 (en) * | 1985-04-27 | 1986-11-05 | Beecham Group Plc | Azabicyclononyl-indazole-carboxamide having 5-HT antagonist activity |
| EP1484321A1 (en) * | 2003-06-03 | 2004-12-08 | Chemagis Ltd. | Process for preparing 1-methylindazole-3-carboxylic acid |
-
2006
- 2006-11-08 WO PCT/IB2006/003146 patent/WO2007054784A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200444A2 (en) * | 1985-04-27 | 1986-11-05 | Beecham Group Plc | Azabicyclononyl-indazole-carboxamide having 5-HT antagonist activity |
| EP1484321A1 (en) * | 2003-06-03 | 2004-12-08 | Chemagis Ltd. | Process for preparing 1-methylindazole-3-carboxylic acid |
Non-Patent Citations (1)
| Title |
|---|
| BERMUDEZ J. ET AL.: "5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives", J. MED. CHEM., vol. 33, no. 7, 1990, pages 1924 - 1929, XP002353768, DOI: doi:10.1021/jm00169a016 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008117282A1 (en) * | 2007-03-27 | 2008-10-02 | Chemagis Ltd. | Polymorph of granisetron base and production process therefor |
| EP2323654A1 (en) * | 2008-08-19 | 2011-05-25 | ScinoPharm Taiwan, Ltd. | Polymorphic form of granisetron hydrochloride and methods of making the same |
| EP2323654A4 (en) * | 2008-08-19 | 2012-10-24 | Scinopharm Taiwan Ltd | Polymorphic form of granisetron hydrochloride and methods of making the same |
| CN103159765A (en) * | 2011-12-15 | 2013-06-19 | 北京嘉林药业股份有限公司 | Indisetron purification method suitable for industrialization |
| CN103159765B (en) * | 2011-12-15 | 2015-06-24 | 北京嘉林药业股份有限公司 | Indisetron purification method suitable for industrialization |
| CN115372487A (en) * | 2021-05-18 | 2022-11-22 | 成都倍特药业股份有限公司 | HPLC (high Performance liquid chromatography) determination method for impurity E in granisetron hydrochloride |
| CN115372487B (en) * | 2021-05-18 | 2023-10-10 | 成都倍特得诺药业有限公司 | HPLC determination method for impurity E in granisetron hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007054784A8 (en) | 2007-08-09 |
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