WO2007026188A1 - Process for the manufacture of antiulceratives - Google Patents
Process for the manufacture of antiulceratives Download PDFInfo
- Publication number
- WO2007026188A1 WO2007026188A1 PCT/IB2005/002568 IB2005002568W WO2007026188A1 WO 2007026188 A1 WO2007026188 A1 WO 2007026188A1 IB 2005002568 W IB2005002568 W IB 2005002568W WO 2007026188 A1 WO2007026188 A1 WO 2007026188A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- och
- sodium
- formula
- benzimidazole
- pantoprazole
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 230000000767 anti-ulcer Effects 0.000 title abstract description 5
- 230000003647 oxidation Effects 0.000 claims abstract description 16
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 12
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 150000001350 alkyl halides Chemical group 0.000 claims description 5
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 claims description 5
- 229960004048 pantoprazole sodium Drugs 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims 3
- 230000001590 oxidative effect Effects 0.000 claims 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 abstract description 13
- 229960005019 pantoprazole Drugs 0.000 abstract description 11
- 239000003513 alkali Substances 0.000 abstract description 7
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 6
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 abstract description 6
- 229960003174 lansoprazole Drugs 0.000 abstract description 5
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 abstract description 5
- 229960000381 omeprazole Drugs 0.000 abstract description 5
- 229960004157 rabeprazole Drugs 0.000 abstract description 5
- 229910052708 sodium Inorganic materials 0.000 abstract description 4
- 239000011734 sodium Substances 0.000 abstract description 4
- PLITYYGQMDTHMM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfanyl)-1h-benzimidazole Chemical class N=1C2=CC=CC=C2NC=1SCC1=CC=CC=N1 PLITYYGQMDTHMM-UHFFFAOYSA-N 0.000 abstract description 3
- HBDKFZNDMVLSHM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfinyl)-1h-benzimidazole Chemical class N=1C2=CC=CC=C2NC=1S(=O)CC1=CC=CC=N1 HBDKFZNDMVLSHM-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000012535 impurity Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 150000003457 sulfones Chemical class 0.000 description 6
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 239000003518 caustics Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- -1 3,4-dimethoxy-2-pyridinyl Chemical group 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- UKILEIRWOYBGEJ-UHFFFAOYSA-N 6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfanyl]-1h-benzimidazole Chemical compound COC1=CC=NC(CSC=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC UKILEIRWOYBGEJ-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 2
- 150000001556 benzimidazoles Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000001174 sulfone group Chemical group 0.000 description 2
- AKUNSTOMHUXJOZ-UHFFFAOYSA-N 1-hydroperoxybutane Chemical compound CCCCOO AKUNSTOMHUXJOZ-UHFFFAOYSA-N 0.000 description 1
- YYRIKJFWBIEEDH-UHFFFAOYSA-N 2-(chloromethyl)-3,4-dimethoxypyridine;hydrochloride Chemical compound [Cl-].COC1=CC=[NH+]C(CCl)=C1OC YYRIKJFWBIEEDH-UHFFFAOYSA-N 0.000 description 1
- HJMVPNAZPFZXCP-UHFFFAOYSA-N 5-(difluoromethoxy)-1,3-dihydrobenzimidazole-2-thione Chemical compound FC(F)OC1=CC=C2NC(=S)NC2=C1 HJMVPNAZPFZXCP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JNOJDURFZLCLSX-UHFFFAOYSA-N O.O.O.[Na].[Na] Chemical compound O.O.O.[Na].[Na] JNOJDURFZLCLSX-UHFFFAOYSA-N 0.000 description 1
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 150000002751 molybdenum Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to an improved process for the preparation of antiulcerative agents, e.g., Pantoprazole, Lansoprazole, Omeprazole and Rabeprazole etc. It provides a process for preparing 2-(2-pyridylmethyl-sulfinyl)benzimidazole compounds by subjecting 2-(2-pyridylmethyl- thio)benzimidazole compounds to oxidation with sodium hypochlorite solution in presence of an alkali in aqueous haloalkanes.
- the products obtained having general Formula I have almost negligible amount ofsulfone impurity.
- Pyridine-2-yl-methylsulfmyl-lH-benzimidazole derivatives such as 5-Difluoromethoxy-2- [(3,4-dimethoxy-2-pyridinyl)-methyI sulfinyl]-lH-benzimidazole (Pantoprazole), 2-[3-Methyl-4- (2 5 2,2-trifluoroethoxy)-2-pyridinyl)methyl sulfinyl]-lH-benzimidazole (Lansoprazole), 5-Methoxy- 2 ⁇ [(4-methoxy-3,5-dimethyl-2 ⁇ pyridinyl)methyl sulfmyl]-lH-benzimidazole (Omeprazole), and 2- [[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methylsulfmyl]-lH-benzimidazole (Rabeprazole) are H+/K+ ATPase
- Pantoprazole Sodium is an irreversible proton pump inhibitor which was developed by Byk Gulden Lamberg Chemiche Fabrik GmbH and disclosed in U.S. Patent No. 4,758,579.
- the process described in the said patent comprises the condensation of 2-Chloromethyl-3,4-dimethoxypyridinium hydrochloride with 5-Difluoromethoxy-2-mercaptobenzimidazole to get the sulfide intermediate which is oxidized with metachloroperoxybenzoic acid in dichloromethane yielding Pantoprazole.
- U.S. Patent No. 4,758,579 in one of its referential example discloses the use of sodium hypochlorite as an oxidizing agent on a different substrate in dioxane and aqueous alkali but there is no disclosure of purity of the product. Moreover, use of dioxane as a solvent itself has disadvantages of its cost and hazards associated with it.
- the process is directed towards preparation of anti-ulcerative agents of benzimidazole derivatives, namely 5-(Difluoromethoxy)- 2- [[( 3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]- 1-H- benzimidazole (Pantoprazole), 2-[[[3-Methyl- 4-(2,2,2-trifluroethoxy)-2-pyridyl]methyl]sulfmyl]benzimidazole (Lansoprazole), 5-Methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole (Omeprazole) and 2-[[[4-(3- Methoxypropoxy) -3-methyl-2-pyridinyl]methyl]- sulfinyl]-lH-benzimidazole (Rabeprazole) having general
- the compounds of Formula I are prepared by subjecting respective 2-(2-pyridylmethyl- thio)benzimidazole compounds to oxidation with sodium hypochlorite solution in presence of an alkali in aqueous haloalkanes.
- the present invention has the advantage of simple reaction conditions, use of cheap and readily available reagents and solvents and efficient work-up procedure that leads to isolation of high purity product (purity above 99%).
- the invention further provides a method for conversion of Pantoprazole to Pantoprazole Sodium Sequihydrate using a single solvent and aqueous sodium hydroxide as the source of sodium.
- Final products obtained in the present invention having Formula I are almost negligible amount of sulfone impurity.
- the present invention relates to a process for the preparation of anti-ulcerative agents, e.g., 5- (Difluoromethoxy)- 2- [[( 3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]- 1-H- benzimidazole (Pantoprazole), 2-[[[3-Methyl-4-(2,2,2-trifluroethoxy)-2-pyridyl]methyl]sulfmyl]benzimidazole (Lansoprazole), 5 -Methoxy-2- [[(4-methoxy-3 ,5 -dimethyl-2-pyridmyl)methyl] sulfmyl] - 1 H- benzimidazole (Omeprazole) and 2-[[[4-(3-Methoxypropoxy) -3-methyl-2-pyridinyl]rnethyl]- sulfinyl]-lH-benzimidazole (Rabeprazol
- the present invention provides a method for preparing compounds having Formula I from 2- (2- ⁇ yridylmethylthio)benzimidazole compounds of Formula II,
- the oxidation of Formula II compounds with sodium hypochlorite yields compounds having Formula I.
- This step involves making a suspension of cold mixture of compounds of Formula II in an aqueous organic solvent in a basic medium.
- Suitable bases include, but not limited to, sodium and potassium hydroxide.
- Suitable organic solvents include, but are not limited to halo-alkanes, preferably dichloromethane, dichloroethane, chloroform and carbon tetrachloride etc.
- Suitable catalyst involved in the oxidation step include, but are not limited to, triethylbenzyl ammonium chloride, etc.
- sodium hypochlorite solution taken in caustic lye is added to the above solution at low temperature.
- the addition of oxidizing agent is performed at about O to 2O 0 C.
- the concentration of sodium hypochlorite solution used for oxidation purpose is between about 5 to 50%, more preferably between about 5 - 20%.
- the reaction mixture is stirred till tMe Oxidation is completed.
- the reaction time for oxidation is between about 10 minutes and 10 hours. More particularly the reaction time is between about 30 minutes to 5 hours.
- product is isolated using general extraction methods.
- the present invention has the advantage of simple reaction conditions, use of cheap and readily available reagents and solvents and efficient work-up procedure that leads to isolation of high purity product (purity above 99%).
- the invention further provides a method for conversion of Pantoprazole to Pantoprazole Sodium Sequihydrate using a single solvent and aqueous sodium hydroxide as the source of sodium.
- U.S. Patent No. 4,758,579 discloses the use of chlorinated solvent in combination with alcohol for the preparation of Pantoprazole Sodium.
- their method requires anti-solvent in large quantity such as isopropyl ether for the precipitation of the product from the reaction mass.
- the present invention discloses the use of single solvent ethyl acetate and aqueous sodium hydroxide as a source of sodium for the reaction. There is no requirement of anti- solvent for the precipitation of the product.
- the product is isolated by filtering the reaction slurry obtained by stirring at 20 0 C and washing the wet solid with ethyl acetate.
- the product obtained after drying is of high purity (about 99.9%) and having no single impurity more than 0.1% thus meeting the highest quality ICH (International Conference on Harmonization) norms.
- Example-1 product (4.0 gm) was suspended in ethyl acetate (25 ml) and aqueous NaOH (10% 5.0 ml) was added. The resulting solution was charcolized and filtered. The filtrate was stirred at 20°C and the resulting slurry was filtered, solid washed with ethyl acetate and dried under vacuum (Yield 4.0 gm, Purity 99.9% by HPLC).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to an improved process for the preparation of antiulcerative compounds, e.g., Pantoprazole, Lansoprazole, Omeprazole and Rabeprazole etc. The process provides a method for preparing 2-(2-pyridylmethyl-sulfinyl)benzimidazole compounds by subjecting 2-(2-pyridylmethyl-thio)benzimidazole compounds to oxidation with sodium hypochlori solution in presence of an alkali.
Description
PROCESS FOR THE MANUFACTURE OF ANTIULCERATIVES
FILED OF THE INVENTION
The present invention relates to an improved process for the preparation of antiulcerative agents, e.g., Pantoprazole, Lansoprazole, Omeprazole and Rabeprazole etc. It provides a process for preparing 2-(2-pyridylmethyl-sulfinyl)benzimidazole compounds by subjecting 2-(2-pyridylmethyl- thio)benzimidazole compounds to oxidation with sodium hypochlorite solution in presence of an alkali in aqueous haloalkanes. The products obtained having general Formula I have almost negligible amount ofsulfone impurity.
Formula I
wherein, R1 = H; R2 = H, CH3; R3 = -OCH3, -OCH2CF3, -OCH2CH2CH2OCH3; R4 = CH3, -OCH3 and R5 = H, -OCH3, -OCHF2
BACKGROUND OF THE INVENTION
Pyridine-2-yl-methylsulfmyl-lH-benzimidazole derivatives such as 5-Difluoromethoxy-2- [(3,4-dimethoxy-2-pyridinyl)-methyI sulfinyl]-lH-benzimidazole (Pantoprazole), 2-[3-Methyl-4- (252,2-trifluoroethoxy)-2-pyridinyl)methyl sulfinyl]-lH-benzimidazole (Lansoprazole), 5-Methoxy- 2~[(4-methoxy-3,5-dimethyl-2~pyridinyl)methyl sulfmyl]-lH-benzimidazole (Omeprazole), and 2- [[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methylsulfmyl]-lH-benzimidazole (Rabeprazole) are H+/K+ ATPase inhibitors used for treatment of diseases caused due to increased gastric acid secretion.
Pantoprazole Sodium is an irreversible proton pump inhibitor which was developed by Byk Gulden Lamberg Chemiche Fabrik GmbH and disclosed in U.S. Patent No. 4,758,579. The process described in the said patent comprises the condensation of 2-Chloromethyl-3,4-dimethoxypyridinium hydrochloride with 5-Difluoromethoxy-2-mercaptobenzimidazole to get the sulfide intermediate
which is oxidized with metachloroperoxybenzoic acid in dichloromethane yielding Pantoprazole. The main disadvantages of this process are formation of sulphone analogue which is difficult to remove, use of metachloroperoxybenzoic acid which is a costly reagent and that gives metachlorobenzoic acid as a byproduct thus increasing the impurity level.
Use of several other oxidizing agents have been reported in different patents for oxidation of sulphide to sulphoxides such as tert. Butyl hydroperoxide or oxone (U.S. Publication No. 2003036554), sodiurnpercarbonate in presence of molybdenum salt as a catalyst (WO 2001068594), sodium perborate (EP 1071678), etc. But all these reagents have either disadvantages of high cost or impurities such as sulphone analogue formation during the oxidation.
U.S. Patent No. 4,758,579 in one of its referential example discloses the use of sodium hypochlorite as an oxidizing agent on a different substrate in dioxane and aqueous alkali but there is no disclosure of purity of the product. Moreover, use of dioxane as a solvent itself has disadvantages of its cost and hazards associated with it.
In an article of J. Med. Chem. 35, 1049 to 1057 (1992) which reveals the preparation of Pantoprazole and derivatives, the use of sodium hypochlorite is disclosed for the oxidation of sulfide to sulfoxide on a different substrate in ethyl acetate and aqueous alkali. However, purity of the obtained product is not disclosed. Moreover, the use of alkali with ethyl acetate is associated with risk of degradation of ethyl acetate resulting in complex solvent system and difficulty in controlling the reaction and work-up pH.
SUMMARY OF THE INVENTION
According to one embodiment of the present invention the process is directed towards preparation of anti-ulcerative agents of benzimidazole derivatives, namely 5-(Difluoromethoxy)- 2- [[( 3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]- 1-H- benzimidazole (Pantoprazole), 2-[[[3-Methyl- 4-(2,2,2-trifluroethoxy)-2-pyridyl]methyl]sulfmyl]benzimidazole (Lansoprazole), 5-Methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole (Omeprazole) and 2-[[[4-(3- Methoxypropoxy) -3-methyl-2-pyridinyl]methyl]- sulfinyl]-lH-benzimidazole (Rabeprazole) having general Formula I as shown below:
Formula I
wherein, R1 = H; R2 = H5 CH3; R3 = -OCH3, -OCH2CF3, -OCH2CH2CH2OCH3; R4 = CH3, -OCH3 and R5 = H, -OCH3, -OCHF2
The compounds of Formula I, are prepared by subjecting respective 2-(2-pyridylmethyl- thio)benzimidazole compounds to oxidation with sodium hypochlorite solution in presence of an alkali in aqueous haloalkanes.
The present invention has the advantage of simple reaction conditions, use of cheap and readily available reagents and solvents and efficient work-up procedure that leads to isolation of high purity product (purity above 99%). The invention further provides a method for conversion of Pantoprazole to Pantoprazole Sodium Sequihydrate using a single solvent and aqueous sodium hydroxide as the source of sodium. Final products obtained in the present invention having Formula I are almost negligible amount of sulfone impurity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of anti-ulcerative agents, e.g., 5- (Difluoromethoxy)- 2- [[( 3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]- 1-H- benzimidazole (Pantoprazole), 2-[[[3-Methyl-4-(2,2,2-trifluroethoxy)-2-pyridyl]methyl]sulfmyl]benzimidazole (Lansoprazole), 5 -Methoxy-2- [[(4-methoxy-3 ,5 -dimethyl-2-pyridmyl)methyl] sulfmyl] - 1 H- benzimidazole (Omeprazole) and 2-[[[4-(3-Methoxypropoxy) -3-methyl-2-pyridinyl]rnethyl]- sulfinyl]-lH-benzimidazole (Rabeprazole) having general Formula I as shown below:
Formula I
The present invention provides a method for preparing compounds having Formula I from 2- (2-ρyridylmethylthio)benzimidazole compounds of Formula II,
Formula II
wherein, R1 = H; R2 = H, CH3; R3 = -OCH3, -OCH2CF3, -OCH2CH2CH2OCH3; R4 = CH3, -OCH3 and R5 = H, -OCH3, -OCHF2
The oxidation of Formula II compounds with sodium hypochlorite yields compounds having Formula I. This step involves making a suspension of cold mixture of compounds of Formula II in an aqueous organic solvent in a basic medium. Suitable bases include, but not limited to, sodium and potassium hydroxide. Suitable organic solvents include, but are not limited to halo-alkanes, preferably dichloromethane, dichloroethane, chloroform and carbon tetrachloride etc. Suitable catalyst involved in the oxidation step include, but are not limited to, triethylbenzyl ammonium chloride, etc. To the resulting reaction mass, sodium hypochlorite solution taken in caustic lye is added to the above solution at low temperature. The addition of oxidizing agent is performed at about O to 2O0C. The concentration of sodium hypochlorite solution used for oxidation purpose is between about 5 to 50%, more preferably between about 5 - 20%. The reaction mixture is stirred till tMe Oxidation is completed. The reaction time for oxidation is between about 10 minutes and 10 hours. More particularly the reaction time is between about 30 minutes to 5 hours. After completion of the reaction, product is isolated using general extraction methods.
It has been found that oxidation of Pantoprazole sulfide intermediate in chlorinated solvent such as dichloromethane, chloroform or dichloroethane, most preferably in dichloromethane using sodium hypochlorite solution as oxidizing agent in presence of alkali at zero or below 0°C temperature gives very clean reaction of sulfide oxidation with negligible formation of sulfone impurity. If peroxyacetic acid is used for the same purpose the sulfone impurity formation is 3 to 4% and with m-Chloroperoxybenzoic acid, sulfone formation in the reaction is also in the same range irrespective of temperature and other reaction conditions. To remove the sulfone analogue, the losses in repeated re-crystallization to bring it into pharmaceutically accepted limits is too high. Table- 1 shows the sulfone analogue formation using different oxidizing agents.
The present invention has the advantage of simple reaction conditions, use of cheap and readily available reagents and solvents and efficient work-up procedure that leads to isolation of high purity product (purity above 99%). The invention further provides a method for conversion of Pantoprazole to Pantoprazole Sodium Sequihydrate using a single solvent and aqueous sodium hydroxide as the source of sodium. U.S. Patent No. 4,758,579 discloses the use of chlorinated solvent in combination with alcohol for the preparation of Pantoprazole Sodium. Moreover, their method requires anti-solvent in large quantity such as isopropyl ether for the precipitation of the product from the reaction mass. The present invention discloses the use of single solvent ethyl acetate and aqueous sodium hydroxide as a source of sodium for the reaction. There is no requirement of anti- solvent for the precipitation of the product. The product is isolated by filtering the reaction slurry obtained by stirring at 200C and washing the wet solid with ethyl acetate. The product obtained after drying is of high purity (about 99.9%) and having no single impurity more than 0.1% thus meeting the highest quality ICH (International Conference on Harmonization) norms.
The following examples illustrate the invention in more detail without limiting it.
EXAMPLES EXAMPLE 1
5Φifluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-lH--benzimidazole (Pantoprazole)
5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylthio]-lH-benzimidazole (5.0 gm) was suspended in a cooled mixture of dichloromethane (60 ml) and water (30 ml) containing triethyl benzyl ammonium chloride (0.05 gm) and caustic lye (5.0 ml). To the resulting reaction mass was added a mixture containing sodium hypochlorite solution (12%, 5.5 ml) and caustic lye (0.9 ml) during 1 hour at 0 to 5°C. The reaction mass was further stirred for 4 hours and reaction progress was monitored by HPLC. After completion of reaction, the organic layer was separated and the pH of the aqueous layer was adjusted to 9 to 9.4 with acetic acid and extracted with dichloromethane. The dichloromethane layer was titurated with isopropyl ether and resulting slurry was filtered, the solid thus obtained was washed with isopropyl ether and dried under vacuum (Yield 4.2 gm, purity 99% by HPLC).
EXAMPLE 2
5-Difluoromethoxy-2-[(3,4-dimethoxy-2~pyridniyl)methylsulfinyl)]-lH-benzimidazole sodium sesquihydrate (Pantoprazole Sodium Sesquihydrate)
The Example-1 product (4.0 gm) was suspended in ethyl acetate (25 ml) and aqueous NaOH (10% 5.0 ml) was added. The resulting solution was charcolized and filtered. The filtrate was stirred at 20°C and the resulting slurry was filtered, solid washed with ethyl acetate and dried under vacuum (Yield 4.0 gm, Purity 99.9% by HPLC).
Claims
1. A process for preparing compounds having Formula I,
Formula I
Formula II
wherein, R1 = H; R2 = H, CH3; R3 = -OCH3, -OCH2CF3, -OCH2CH2CH2OCH3; R4 = CH3, -OCH3 and R5 = H, -OCH3, -OCHF2
with an oxidizing agent in a suitable solvent or mixture of solvents.
2. The process of claim 1 , wherein oxidizing agent is sodium hypochlorite.
3. The process of claim 2, wherein concentration of sodium hypochlorite solution is between about 5-50 %.
4. The process of claim 3, wherein more preferably concentration of sodium hypochlorite solution is between about 5 to about 20%.
5. The process of claim 1, wherein oxidation step is carried out in aqueous organic solvent.
6. The process of claim 5, wherein organic solvent is haloalkane.
7. The process of claim 6, wherein more preferably haloalkanes are dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
8. The process of claim 7, wherein more preferably haloalakne is dichloromethane.
9. The process of claim 1, wherein oxidation step is carried out in presence of an inorganic base.
10. The process of claim 9, wherein preferably inorganic bases are sodium and potassium hydroxide.
11. The process of claim 10, wherein more preferably inorganic base is sodium hydroxide.
12. The process of claim 1, wherein the catalyst used is triethylbenzylammonium chloride.
13. The process of claim 1, wherein oxidation step is carried in between about 10 minutes to 10 hours.
14. The process of claim 13, where in more particularly reaction time is between 30 minutes to 5 hours.
15. The process of claim 1, wherein Pantoprazole sodium purity is more than 99 %.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2005/002568 WO2007026188A1 (en) | 2005-09-01 | 2005-09-01 | Process for the manufacture of antiulceratives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2005/002568 WO2007026188A1 (en) | 2005-09-01 | 2005-09-01 | Process for the manufacture of antiulceratives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007026188A1 true WO2007026188A1 (en) | 2007-03-08 |
Family
ID=37808490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2005/002568 WO2007026188A1 (en) | 2005-09-01 | 2005-09-01 | Process for the manufacture of antiulceratives |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2007026188A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009010937A1 (en) * | 2007-07-17 | 2009-01-22 | Ranbaxy Laboratories Limited | Process for the preparation op pantoprazole sodium and pantoprazole sodium sesquihydrate |
| WO2009066317A3 (en) * | 2007-08-20 | 2009-07-23 | Macleods Pharmaceuticals Ltd | Process for the preparation of pantoprazole sodium |
| ES2326401A1 (en) * | 2007-12-28 | 2009-10-08 | Laboratorios Viñas | Procedure for manufacturing 2 - (((3-methyl-4- (3-metoxypropoxy) -2-piridyl) methyl) sulfinyl) -1H-benzymidazole (Machine-translation by Google Translate, not legally binding) |
| US7683177B2 (en) | 2003-06-10 | 2010-03-23 | Teva Pharmaceutical Industries Ltd | Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole |
| WO2009066321A3 (en) * | 2007-10-03 | 2011-01-06 | Ipca Laboratories Limited | Process for optically active sulfoxide compounds |
| WO2008155780A3 (en) * | 2007-06-21 | 2011-03-31 | Matrix Laboratories Ltd | Improved process for the preparation of pure rabeprazole |
| CN103044399A (en) * | 2011-10-12 | 2013-04-17 | 北大方正集团有限公司 | Preparation method of rabeprazole and sodium salts thereof |
| EP3187494A1 (en) | 2015-12-30 | 2017-07-05 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of pantoprazole sodium sesquihydrate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758579A (en) * | 1984-06-16 | 1988-07-19 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Fluoroalkoxy substituted benzimidazoles useful as gastric acid secretion inhibitors |
-
2005
- 2005-09-01 WO PCT/IB2005/002568 patent/WO2007026188A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758579A (en) * | 1984-06-16 | 1988-07-19 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Fluoroalkoxy substituted benzimidazoles useful as gastric acid secretion inhibitors |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7683177B2 (en) | 2003-06-10 | 2010-03-23 | Teva Pharmaceutical Industries Ltd | Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole |
| WO2008155780A3 (en) * | 2007-06-21 | 2011-03-31 | Matrix Laboratories Ltd | Improved process for the preparation of pure rabeprazole |
| WO2009010937A1 (en) * | 2007-07-17 | 2009-01-22 | Ranbaxy Laboratories Limited | Process for the preparation op pantoprazole sodium and pantoprazole sodium sesquihydrate |
| WO2009066317A3 (en) * | 2007-08-20 | 2009-07-23 | Macleods Pharmaceuticals Ltd | Process for the preparation of pantoprazole sodium |
| WO2009066321A3 (en) * | 2007-10-03 | 2011-01-06 | Ipca Laboratories Limited | Process for optically active sulfoxide compounds |
| ES2326401A1 (en) * | 2007-12-28 | 2009-10-08 | Laboratorios Viñas | Procedure for manufacturing 2 - (((3-methyl-4- (3-metoxypropoxy) -2-piridyl) methyl) sulfinyl) -1H-benzymidazole (Machine-translation by Google Translate, not legally binding) |
| ES2326401B1 (en) * | 2007-12-28 | 2010-06-24 | Laboratorios Viñas | PROCEDURE FOR MANUFACTURING 2 - ((((3-METHYL-4- (3-METOXIPROPOXI) -2-PIRIDIL) METHYL) SULFINIL) -1H-BENZIMIDAZOL. |
| CN103044399A (en) * | 2011-10-12 | 2013-04-17 | 北大方正集团有限公司 | Preparation method of rabeprazole and sodium salts thereof |
| CN103044399B (en) * | 2011-10-12 | 2014-08-06 | 北大方正集团有限公司 | Preparation method of rabeprazole and sodium salts thereof |
| EP3187494A1 (en) | 2015-12-30 | 2017-07-05 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of pantoprazole sodium sesquihydrate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7439367B2 (en) | Pharmaceutical process and compounds prepared thereby | |
| EP1578742B1 (en) | Process for preparing optically pure active compounds | |
| NO324257B1 (en) | Process for the preparation of benzimidazole-type compounds | |
| KR101169471B1 (en) | Method for producing (S) -pantoprazole | |
| WO2007026188A1 (en) | Process for the manufacture of antiulceratives | |
| WO2009116072A2 (en) | Process for preparation of pyridinylmethylsulphinyl benzimidazole compounds and pyridine intermediates | |
| US8962851B2 (en) | One-pot process for the preparation of benzimidazole derivatives | |
| WO2007129328A2 (en) | Process for preparing 2-[pyridinyl]sulfinyl-substituted benzimidazoles | |
| JP2008137895A (en) | Method for preparing s-pantoprazole | |
| HK1078863B (en) | Process for preparing (s)-pantoprazole | |
| HK1078864B (en) | Process for preparing optically pure active compounds | |
| HK1125098A1 (en) | Isotopically substituted proton pump inhibitors | |
| HK1125098B (en) | Isotopically substituted proton pump inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 05782957 Country of ref document: EP Kind code of ref document: A1 |