WO2006049486A1 - Méthode de synthèse de 2-(2-pyridylméthoylsulphinyl)-1h-benzimidazoles substitués - Google Patents

Méthode de synthèse de 2-(2-pyridylméthoylsulphinyl)-1h-benzimidazoles substitués Download PDF

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Publication number
WO2006049486A1
WO2006049486A1 PCT/NL2005/000649 NL2005000649W WO2006049486A1 WO 2006049486 A1 WO2006049486 A1 WO 2006049486A1 NL 2005000649 W NL2005000649 W NL 2005000649W WO 2006049486 A1 WO2006049486 A1 WO 2006049486A1
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Prior art keywords
reaction
substituted
benzimidazole
compound
process according
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PCT/NL2005/000649
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English (en)
Inventor
Janmejay Rajnikant Vyas
Kasa Mallik Yadav
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Dishman Pharmaceuticals And Chemicals Ltd.
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Publication of WO2006049486A1 publication Critical patent/WO2006049486A1/fr

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    • 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 substituted 2-(2-pyridylmethylsulphinyl)-l-H-benzimidazoles and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • MCPBA 3-chloroperoxybenzoic acid
  • EP-A-533.752, US 5,386,032, ES-A-043.816 and EP-A- 484.265 magnesium monoperoxyphthalate
  • MMPP magnesium monoperoxyphthalate
  • ammonium molybdate e.g. EP-A-484.265
  • iodosobenzene e.g. ES-A- 539.793
  • methyl iodosobenzene e.g. ES-A-540.147
  • sodium periodate ES-A- 550.070
  • vanadium oxide EP-A-302.720
  • WO-A-2004/063188 teaches the oxidation of a sulphide compound in the presence of a hypohalite salt at pH 9 - 12 in aqueous conditions.
  • the reaction is performed in the presence of a catalyst from the group consisting of pyridine, di-isopropylethylamine and N,N-dimethylaminopyridine in order to avoid deformation of undesirable by-products.
  • a catalyst from the group consisting of pyridine, di-isopropylethylamine and N,N-dimethylaminopyridine in order to avoid deformation of undesirable by-products.
  • WO-A-03/008406 suggests to extract the reaction mixture with aqueous alkaline solutions after completion of the oxidation reaction.
  • a sulphinylbenzimidazole is obtained having variable amounts of sulphone impurities incorporated therein, the minimum amount of sulfon in the residue being 0.26 %, but in most reported cases much higher.
  • the process is cost-effective, eco-friendly and suitable for upscaling.
  • PTC phase transfer catalyst
  • the mechanism may be the following: the phase transfer catalyst forms a complex with the hypohalite oxidation agent in the aqueous phase, which complex is then transported from the aqueous phase to the organic phase containing the substituted 2-(2-pyridylmethylthio)-l-H-benzimidazole compound. Once formed, the sulphoxide or sulphinyl compound transfers from the organic phase to the aqueous phase, where it is not susceptible to further oxidation. Hence, the undesired over-oxidation of sulphoxide is therewith controlled. In this process, oxidation agent and oxidising molecule are present in the same (organic) phase, which accelerates the oxidation reaction, and makes the reaction neat and clean.
  • the PTC advantageously avoids large formation of sulphone impurities.
  • the invention particularly relates to a process for the preparation of a substituted 2-(2-pyridylmethylsulphinyl)-l-H-benzimidazole involving the reaction of a corresponding 2-(2-pyridylmethylthio)-l-H-benzimidazole compound, given by the formula:
  • R 1 and R 3 are hydrogen, methyl or Ci ⁇ alkoxy
  • R 2 is substituted or unsubstituted C 1-4 alkoxy
  • R 4 is hydrogen or substituted or unsubstituted C 1-4 alkoxy, with a hypohalite oxidation agent in the presence of a phase transfer catalyst, wherein the reaction involves a biphasic reaction mixture containing an aqueous phase and an organic phase.
  • the substituted C 1-4 alkoxy group in formula (II) is preferably completely or predominantly substituted by fluorine, chlorodifluoromethyl, or chlorotrifluoroethylenedioxy.
  • Omeprazole (A), Lansoprazole (B), Pantoprazole (C) or Rabeprazole (D) is obtained.
  • the process of the invention is especially suitable for the preparation of Omeprazole.
  • Pharmaceutically acceptable salts, hydrates and solvates, preferably at least the salts of the sulphinyl compound (I) are also included.
  • the hypohalite oxidation agent is preferably provided to the reaction mixture as an aqueous solution of an alkali metal or alkaline earth metal hypohalite. It is preferably selected from the group consisting of sodium, potassium or calcium hypochlorite or hypobromite.
  • the oxidation agent is preferably potassium or sodium hypochlorite, most preferably sodium hypochlorite.
  • the concentration of the hypohalite oxidation agent in the aqueous solution is preferably 2 - 30 wt%. It is preferred to use an aqueous hypohalite solution having a concentration in the range of 2 to 5 %, for ease of handling.
  • the amount of hypohalite oxidation agent employed in the process is in the range of 0.8 to 2.0, more preferably 0.95 - 1.5, most preferably 1.0 - 1.5, in particular 1.1 - 1.4 moles per mole of the 2-(2-pyridylmethylthio)-l-H-benzimidazole compound having formula (II).
  • the amount of hypohalite oxidation agent in the course of the reaction can be determined using conventional starch iodide tests, and an excess of hypohalite can be deactivated using a thiosulphate solution at the end of the reaction.
  • the reaction is preferably performed at alkaline conditions, preferably at pH 8.5 - 13, more preferably at least pH 9, most preferably pH 10 - 12.
  • a commercially available hypohalite solution can be employed, but it is advantageous to use a freshly prepared solution typically including a suitable amount of free corresponding alkali or alkali earth metal hydroxide, carbonate, bicarbonate or amine (e.g. ammonia or an organic amine) to control the pH during oxidation at the aforementioned alkaline conditions.
  • the presence of the base not only stabilises the hypohalite, but also exhibits an advantageous stabilising effect on the benzimidazole sulphinyl products which are known to be unstable in acidic conditions.
  • a solution containing the alkaline material can be added to the suspension or solution of a precursor sulphide compound before oxidation of the oxidation agent.
  • the base is sodium hydroxide.
  • the aqueous hypohalite solution is typically added to an organic solvent comprising the sulphide precursor compound of formula (II) dissolved or suspended therein, or a mixture of organic solvents, over a time period ranging from several minutes to several hours, depending on the strength of the hypohalite solution and the exothermicity of the reaction. It is preferred to perform the addition slowly and continuously over a period from 30 minutes to 4 hours, with the total time taken for completion of the reaction ranging from 1 to 10 hours, preferably 1 - 4 hours. During the addition the temperature is preferably maintained between 0 and 20 0 C.
  • the phase transfer catalyst may be a quaternary ammonium or phosphonium salt, preferably a quaternary ammonium salt, more preferably a tetra-ahcylammonium salt having C 2 -C 8 -alkyl, or benzyl-trialkylammonium salt, wherein the alkyl is C 2 -Cg.
  • the counter anion is preferably a halide or a hydrogen sulphate, more preferably Br " or Cl " .
  • the PTC is tetrabutylammonium bromide.
  • the amount of PTC employed is preferably 1.0 - 5.0 wt% of the amount of the sulphide precursor given by formula (II).
  • the reaction further involves a temperature in the range of 0 0 C up to the boiling point of the organic liquid diluent forming the organic phase.
  • a temperature in the range of 0 to 55 0 C Preferably the process is carried out at a temperature in the range of 0 to 55 0 C.
  • the temperature is preferably in the range of 5 to 40
  • 0 C 5 most preferably 10 - 25 °C.
  • the purpose of the biphasic reaction mixture of an aqueous phase and an organic phase is to allow contact between the organic starting compound and the oxidation agent.
  • Any liquid organic diluent which is inert to the reactants and shows limited mutual solvability with the aqueous phase is suitable for the purpose of the invention.
  • aqueous phase is also meant to comprise mixtures of water with an organic solvent substantially miscible therewith, for instance a C 1-4 alcohol, preferably methanol.
  • organic solvent substantially miscible therewith for instance a C 1-4 alcohol, preferably methanol.
  • aqueous phase or “water”
  • water it is understood to comprise also mixtures of water with other polar solvent(s), provided that they form a single, predominantly aqueous phase. It is preferred that water forms more than 50 wt%, more preferably more than 70 wt% of the aqueous phase, including reactants present therein.
  • the organic diluent, forming the other, non-aqueous phase is selected from acetonitrile, methylene dichloride, C 2-6 diols and mixtures thereof.
  • the biphasic reaction mixture is a water/methylene dichloride mixture or a water/acetonitrile mixture.
  • the organic phase and aqueous phase are present in a volume ratio of 3:1 to 1:3, more preferably 2:1 to 1:2.
  • the liquid diluent is added from 5 to 10 volumes in litres per kg sulphide, without taking their densities into account.
  • the invention also relates to substituted 2-(2-pyridylmethylsulphinyl)-l-H- benzimidazole, preferably Omeprazole, Lansoprazole, Pantoprazole or Rabeprazole, or a pharmacologically acceptable salt, hydrate or solvate thereof, wherein the product contains less than 0.2 wt%, more preferably less than 0.1 wt% of sulphone impurities.
  • “Sulphone impurities" in the context of the invention is meant to comprise all compounds containing a sulphone group present in the formulation. ⁇
  • the purification solvent is preferably selected from a (chlorinated) hydrocarbon, an ether, a low molecular weight aliphatic alcohol, or a ketone, more preferably acetonitrile, acetone or ethylacetate.
  • the compounds according to the invention are initially obtained either as free compounds or in the form of salts. These salts can be converted into the free compounds or pharmacologically acceptable salts using methods known to persons skilled in the art.
  • the sulphoxides according to the invention are optically active compounds.
  • the invention therefore also relates both to the enantiomers and to their mixtures and racemats. These can be separated by known methods.
  • the corresponding sulphide precursor given by formula (II) can be applied in the oxidation process as it is commercially available on the market.
  • the reaction can be performed as a two-step reaction process, in which the oxidation step is preceded by an isolation or purification step to obtain the precursor compound (II) in a more purified form.
  • Isolation can involve solvent extraction and direct crystallisation, in aqueous media for instance achieved with acids such as glacial acetic acid along with acetone or ethyl acetate.
  • Such as crystallisation step typically involves a pH of 7 - 9, more preferably 7.5 - 8.
  • the compound of formula (II) is isolated as a free solid by using acid such as glacial acetic acid along with acetone or ethyl acetate.
  • acid such as glacial acetic acid along with acetone or ethyl acetate.
  • the synthesis of the sulphinyl compound of the invention is performed as a one-step or one-pot process, wherein the reaction conditions are selected to perform the oxidation reaction without any intermediate purification or isolation steps directly after the formation of the corresponding 2-(2- pyridylmethylthio)-l-H-benzimidazole compound (II).
  • the invention also relates to a process for the preparation of substituted 2- (2-pyridybnethylsulphinyl)-l-H-benzrmidazole, wherein the aforementioned oxidation reaction immediately succeeds the formation of the corresponding 2-(2- pyridyhnethylthio)-l-H-benzimidazole compound in a one pot synthesis route.
  • the inventino relates to a one-pot synthesis of substituted 2-(2- pyridylmethylsulphinyl)-l-H-benzimidazole, involving a first art-known reaction to form 2-(2-pyridylmethylthio)-l-H-benzimidazole, immediately succeeded in a second step by the above-described oxidation of the 2-(2-pyridylmethylthio)-l-H- benzimidazole compound thus obtained.
  • R 15 R 2 , and R 3 are as previously defined and X is a suitable leaving group, preferably a halogen atom, more preferably a Cl or Br, most preferably a Cl, to obtain a 2-(2-pyridylmethylthio)-l-H-benzimidazole compound given by formula (II), and further oxidising this compound with a hypohalite in presence of phase transfer catalyst as previously described.
  • X is a suitable leaving group, preferably a halogen atom, more preferably a Cl or Br, most preferably a Cl, to obtain a 2-(2-pyridylmethylthio)-l-H-benzimidazole compound given by formula (II), and further oxidising this compound with a hypohalite in presence of phase transfer catalyst as previously described.
  • Alternative synthesis routes for the formation of the precursor compound (II) can be applied, such as taught in US 4,758,579, its contents herein incorporated by reference. The reactants are employed in their free states or as salts
  • the reaction between these reactants is performed in a suitable, preferably polar, protic or aprotic solvent, for instance methanol, isopropanol, dimethyl sulphide, acetone, dimethylformarnide, methylene dichloride, ethylacetate or acetonitrile.
  • a suitable, preferably polar, protic or aprotic solvent for instance methanol, isopropanol, dimethyl sulphide, acetone, dimethylformarnide, methylene dichloride, ethylacetate or acetonitrile.
  • an aqueous solution more preferably at alkaline conditions, typically pH 10 - 13, or a combination of water with an organic solvent miscible with water, more preferably a water/methanol mixture.
  • the second liquid diluent is a water/acetonitrile mixture or a water/methylene dichloride, typically in a volume ratio between 3:1 and 1:3.
  • methylene dichloride thus avoiding further mixing of the solvent for the extraction of compound (II).
  • the first reaction step is preferably carried out at temperature between 0 0 C and the boiling temperature of the solvent, more preferably in the range of 10 - 50°C, even more preferably at a temperature in the range of 15 - 25 °C and more preferably at a temperature in the range of 20 - 30 °C.
  • the second step is performed as outlined above.
  • the details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non- limiting exemplary illustrations.
  • the examples are merely illustrative and do not limit the teaching of this invention and it would be obvious that various modifications or changes in the procedural steps are immediately clear to those skilled in the art without departing from the scope of the invention and shall be consequently encompassed within the ambit and spirit of this approach and scope of the claims.
  • the pH was adjusted to 7.5 to 8.0 with 50% acetic acid.
  • the methylene dichloride layer was separated and the aqueous layer was extracted with 300 ml of methylene dichloride.
  • the solvent was evaporated under vacuum at 35°C and 300 ml of acetonitrile was added at room temperature.
  • the resultant mass was heated to 50-55 0 C to dissolve the residue completely, then cooled to 0-5 0 C and maintained at this temperature for 1.0 hour.
  • the compound was filtered and washed with 2 x 25 ml of acetonitrile. Finally, the compound was dried at 40 - 45 0 C under vacuum for 2-3 hrs.
  • the dry product thus obtained weighed 70 — 75 g (70% yield), purity as determined by HPLC was 98.5 - 99 %.
  • reaction conditions were similar to those described in example Ia, except that 700 ml of water was added to the Rabeprazole sulphide dissolved in methylene dichloride, and only then 2.0 g of the phase transfer catalyst was added at room temperature. 418 ml sodium hypochlorite solution was added as a 5.5% aqueous solution in 45 minutes. The pH was monitored and kept between 11 and 12 using diluted caustic solution (5% NaOH). After heating to 20-25 °C it was stirred for 2-3 hrs.
  • the methylene dichloride layer was separated and the aqueous layer collected. 200 ml of methylene dichloride was added, and the aqueous layer separated. Its pH was adjusted to 7.5 to 8.0 with 50% acetic acid at 10-15 0 C. The content was stirred for 3 hrs at this temperature, and the product filtered and washed with 4 X 25 ml demineralised water. The dry product thus obtained weighed 70 - 75 g (70% yield), purity as determined by HPLC was 99 %.
  • hypochlorite was decomposed using 5% sodium thiosulphate solution (100 ml). The pH was adjusted to 7.5 to 8.0 with 50% acetic acid at 10 -15 0 C. The mass was then extracted with methylene dichloride 3 X 300 ml. The solvent was evaporated under vacuum at 35°C and 300 ml of ethyl acetate was added at RT. This was then heated to 50-55 0 C to dissolve the residue completely. Further it was cooled to 0-5 0 C and maintained at this temperature for 1.0 hr. The compound was then filtered and washed with 2x 25 ml of acetonitrile. The compound was dried at 40 - 45 0 C under vacuum for 2-3 hrs.
  • the dry product thus obtained weighed 65 — 70 g (66% yield), purity as determined by HPLC was 98.5 - 99 %.
  • Example 2b A mixture of 100 g of pantoprazole sulphide, methylene dichloride (600 ml) and demineralised water (400 ml) was cooled to 0- 5 0 C and 2 g TBAB was added at the same temperature. Then 5 % sodium hypochlorite solution in water (430 ml) was charged slowly for 45 minutes and the reaction mixture was stirred for 1 - 2 hours.
  • hypochlorite was decomposed using 5% sodium thiosulphate solution (100 ml).
  • the methylene dichloride layer was separated and extracted with 200 ml methylene dichloride. Then the pH of the aqueous layer was adjusted to 7.5 - 8.0 with 50% acetic acid at 10 — 15°C.
  • the gummy compound was extracted with methylene dichloride 3 X 300 ml, the solvent evaporated under vacuum at 35 temperature and 300 ml of ethyl acetate was added at RT. Then it was heated to 50- 55°C temperature to dissolve the residue completely, cooled to 0-5 0 C temperature and maintained for 1.0 hr.
  • the compound was filtered and washed with 2x 25 ml of acetonitrile. Drying was performed at 40 - 45 0 C under vacuum for 2-3 hrs. The dry product thus obtained weighed 85 - 9O g (65% yield based on 2- chloromethyl-3,4-dimethoxypyridine hydrochloride, purity as determined by HPLC was 98.5 - 99 %.
  • the aqueous layer was filtered through a hyflow bed, which hyflow bed was washed with 2 X 20ml demineralised water.
  • 50% dilute acetic acid solution was added slowly to obtain a pH 7.5 - 8.0 at 10 to 15 0 C.
  • 100 ml acetone was charged at 10 to 15 0 C, and the temperature was raised to 15 to 2O 0 C.
  • stirring at 15 to 2O 0 C the product was filtered and washed with 2 X 50 ml demineralised water. The compound was unloaded.
  • the wet weight was 100 - 125 g. After drying the product weighed 90 g (87%). The powder had a cream or off white colour, and was 99.5 % pure according to HPLC. The single maximum impurity was about 0.1%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention a pour objet un procédé de synthèse d’un 2-(2-pyridylméthylsulphinyl)-1H-benzimidazole substitué qui implique la réaction d'un dérivé de 2-(2-pyridylméthylthio)-1H-benzimidazole adéquat avec un agent d’oxydation hypohalogéné en présence d’un catalyseur par transfert de phase. Cette réaction se fait dans un mélange réactionnel biphasique constitué d'une phase aqueuse et d'une phase organique. La réaction peut aboutir directement à la formation dudit dérivé de 2-(2-pyridylméthylthio)-1H-benzimidazole par un procédé de type one-pot, ce qui évite des étapes de purification coûteuses et longues. La suroxydation du produit de départ, qui aboutit à des sous-produits de type sulphone, est ainsi évitée. Les rendements sont alors plus élevés. La présente invention a donc également pour objet un 2-(2-pyridylméthylsulphinyl)-1H-benzimidazole substitué contenant moins de 0,2 % en masse d’impuretés de type sulphone.
PCT/NL2005/000649 2004-11-08 2005-09-08 Méthode de synthèse de 2-(2-pyridylméthoylsulphinyl)-1h-benzimidazoles substitués WO2006049486A1 (fr)

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IN1200/MUM/2004 2004-11-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044399A (zh) * 2011-10-12 2013-04-17 北大方正集团有限公司 一种雷贝拉唑及其钠盐的制备方法
CN106632251A (zh) * 2016-09-30 2017-05-10 青岛云天生物技术有限公司 一种(s)‑泮托拉唑的制备方法
CN106632248A (zh) * 2016-09-30 2017-05-10 青岛云天生物技术有限公司 一种左旋泮托拉唑钠的制备工艺

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US5708013A (en) * 1987-06-17 1998-01-13 Eisai Co., Ltd. Pyridine derivative and therapeutic agent for ulcer comprising the same
US6423846B1 (en) * 2001-09-28 2002-07-23 Hanmi Pharm. Co., Ltd. High-yield method for preparing lansoprazole
CN1377878A (zh) * 2001-04-04 2002-11-06 中国医学科学院药物研究所 一种亚砜基前体氧化工艺
WO2003008406A1 (fr) * 2001-07-16 2003-01-30 Janssen Pharmaceutica N.V. Procede ameliore de preparation de composes de type benzimidazole
WO2004063188A1 (fr) * 2003-01-15 2004-07-29 Cipla Limited Procede pharmaceutique et composes prepares au moyen de ce procede

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5708013A (en) * 1987-06-17 1998-01-13 Eisai Co., Ltd. Pyridine derivative and therapeutic agent for ulcer comprising the same
CN1377878A (zh) * 2001-04-04 2002-11-06 中国医学科学院药物研究所 一种亚砜基前体氧化工艺
WO2003008406A1 (fr) * 2001-07-16 2003-01-30 Janssen Pharmaceutica N.V. Procede ameliore de preparation de composes de type benzimidazole
US6423846B1 (en) * 2001-09-28 2002-07-23 Hanmi Pharm. Co., Ltd. High-yield method for preparing lansoprazole
WO2004063188A1 (fr) * 2003-01-15 2004-07-29 Cipla Limited Procede pharmaceutique et composes prepares au moyen de ce procede

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DATABASE WPI Section Ch Week 2003, Derwent World Patents Index; AN 2003-222485, XP002365632, "OXIDATION PROCESS SULPHOXIDE BASE PRECURSOR" *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044399A (zh) * 2011-10-12 2013-04-17 北大方正集团有限公司 一种雷贝拉唑及其钠盐的制备方法
CN103044399B (zh) * 2011-10-12 2014-08-06 北大方正集团有限公司 一种雷贝拉唑及其钠盐的制备方法
CN106632251A (zh) * 2016-09-30 2017-05-10 青岛云天生物技术有限公司 一种(s)‑泮托拉唑的制备方法
CN106632248A (zh) * 2016-09-30 2017-05-10 青岛云天生物技术有限公司 一种左旋泮托拉唑钠的制备工艺

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