WO2016134854A1 - Methods for the preparation of topiroxostat and intermediates thereof - Google Patents

Methods for the preparation of topiroxostat and intermediates thereof Download PDF

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Publication number
WO2016134854A1
WO2016134854A1 PCT/EP2016/000343 EP2016000343W WO2016134854A1 WO 2016134854 A1 WO2016134854 A1 WO 2016134854A1 EP 2016000343 W EP2016000343 W EP 2016000343W WO 2016134854 A1 WO2016134854 A1 WO 2016134854A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
topiroxostat
acceptable salt
pharmaceutically acceptable
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PCT/EP2016/000343
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English (en)
French (fr)
Inventor
V. Theocharis Koftis
Efstratios Neokosmidis
Thanos Andreou
Christos STATHAKIS
Petros GKIZIS L.
Original Assignee
Pharmathen S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Pharmathen S.A. filed Critical Pharmathen S.A.
Priority to CN201680023004.9A priority Critical patent/CN107531677A/zh
Priority to JP2017544629A priority patent/JP6811717B2/ja
Publication of WO2016134854A1 publication Critical patent/WO2016134854A1/en

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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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system

Definitions

  • the present invention relates to novel preparation methods for Topiroxostat through novel intermediates.
  • Topiroxostat of formula 1 belongs to a large family of novel 1, 2, 4-triazole compounds and is characterized by a high xanthine oxidase inhibiting activity. It is also useful as a therapeutic agent for hyperuricemia and gout due to hyperuricemia caused by increased production of uric acid. Topiroxostat shows effective reduction in the serum urate level in hyperuricemic patients with or without gout.
  • Topiroxostat or FYX-051 was first developed by Fuji Yakuhin Co. Ltd. and its synthesis is described in EP1471065B. In this first synthesis of Topiroxostat 1, the introduction of the cyano group on pyridyl ring takes place in the first step prior to the condensation reaction.
  • CN103724329B described an alternative process for the preparation of Topiroxostat, as shown in the next scheme.
  • the present invention discloses novel processes for the preparation of Topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, through novel intermediates, avoiding the use of dangerous reagents or long and tedious processes.
  • the present invention discloses a novel process for the preparation of Topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, that avoids the use of any cyanide species such as NaCN, HCN, KCN, TSMCN, CuCN, Zn(CN) 2 for the cyanation of the pyridyl ring.
  • This novel process leads to the preparation of Topiroxostat employing a new way for the introduction of the cyano group on the pyridyl ring using cheaper and safer reagents.
  • the present invention discloses a new process for the preparation of Topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof comprising the steps of: a) reacting compound of formula 3 with compound of formula 5 in the presence of a base to form compound of formula 6
  • Ri and R 2 are each independently selected from hydrogen or a carbamoyl group, with the proviso that R
  • Ri and R 2 represent either hydrogen or carbamoyl group, throughout the whole invention, unless otherwise specified.
  • Another embodiment of the present invention is the direct conversion of compound of formula 6, wherein R, and R 2 are defined as above, to Topiroxostat of formula 1 or any pharmaceuticall acceptable salt, hydrate, solvate or polymorph thereof.
  • a further embodiment of the present invention is the introduction of the cyano group on the pyridyl ring without the use of cyanide species.
  • the cyanation of the pyridyl group is performed by introducing a carbamoyl group and then direct conversion to cyano group according to the present invention.
  • Another embodiment of the present invention discloses the conversion of either Ri group or R 2 group, when either of them is not hydrogen, to cyano group in any step of the process.
  • the present invention discloses novel methods for the production of Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, through novel intermediates.
  • the present invention discloses a novel process for the preparation of Topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, that avoids the use of any cyanide species, leading to major environmental concerns and utilizes a short and efficient synthetic procedure.
  • This novel process for Topiroxostat employs a different method for the cyanation on the pyridyl ring characterized by the use of a group which can easily be converted into cyano group.
  • the present invention describes a novel process for the preparation of Topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof comprising the steps of: a) reacting compound of formula 3a, wherein Ri is a carbamoyl group, with compound of formula 5b, wherein R 2 is hydrogen, in the presence of a base to form compound of formula 6b, wherein Ri is a carbamoyl group and R 2 is hydrogen ;
  • the present invention provides novel intermediates of formulae 6 and 7. These novel intermediates may be employed in the processes disclosed in the present invention as salts as well, depending on the reagents used in the course of the process. Accordingly, compounds of formulae 6 and 7 may be isolated as salts, when acids are used in steps a or b.
  • the present invention provides a method for the preparation of novel intermediate of formula 6, from compounds of formula 3 and 5, as described above.
  • the present invention provides a method for the preparation of novel intermediate of formula 7, from compound of formula 6, as described above. Said method may further comprise preparation of compound of formula 6 from compounds of formula 3 and 5, as described above.
  • steps (b) or (b') and (c) can be performed without isolating any intermediate.
  • Another embodiment of the present application is the conversion of compound of formula 6b or 6c prepared as described above, to Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
  • the formation of triazole ring and the conversion of carbamoyl group can be performed simultaneously according to the process described in the present invention.
  • a particular embodiment of the present application is that the introduction of carbamoyl group, can be performed in any step of the processes described above.
  • Another embodiment of the present invention is that the conversion of carbamoyl group into cyano group can be performed in any step of the new process.
  • a further embodiment of the present invention is the introduction of carbamoyl group on the pyridyl ring of 4-cyano-pyridine to form compound of formula 3b.
  • An embodiment of the present invention is the introduction of the carbamoyl group on isonicotinohydazide's pyridil ring to form compound of formula 5a wherein R 2 is a carbamoyl group.
  • the improvement of all the above described processes, with respect to prior art methods, is the introduction of the carbamoyl group on the pyridyl group and its conversion to cyano group in the absence of highly toxic reagents and by employing less costly starting materials.
  • the present invention provides a quick and efficient process, wherein steps a and b or a' and b' can preferably be performed without isolation of intermediates.
  • the carbamoylation step can be accomplished using formamide (HCONH 2 ) in the presence of an acid or a radical initiator.
  • the carbamoylation takes place in the presence of an inorganic acid such as nitric acid, sulfuric acid or similar inorganic acid, an organic acid such as formic acid, acetic acid or similar organic acid.
  • an inorganic acid such as nitric acid, sulfuric acid or similar inorganic acid
  • an organic acid such as formic acid, acetic acid or similar organic acid.
  • the introduction of the carbamoyl group can be accomplished in the presence of a radical initiator such as CAN (cerium ammonium nitrate) or similar reagents.
  • the carbamoylation reaction can be catalyzed by hydroxyl radicals such as TEMPO [(2,2,6,6- Tetramethylpiperidin-l-yl)oxyl], PINO (phthalimide-N-oxyl) or similar reagents, derived from TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-l-oxyl), NHPI (N- hydroxyphthalimide) or similar reagents.
  • hydroxyl radicals such as TEMPO [(2,2,6,6- Tetramethylpiperidin-l-yl)oxyl], PINO (phthalimide-N-oxyl) or similar reagents, derived from TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-l-oxyl), NHPI (N- hydroxyphthalimide) or similar reagents.
  • step (a) or (a') of any of the previous embodiments the compound of formula 3a or 3b is converted to the corresponding iminoether in the presence of an alcohol under basic or acidic conditions.
  • the alcohol may be for example methanol, ethanol or similar lower alkyl alcohol, which in the presence of a base is easily converted to the corresponding alkoxide.
  • an alcohol such as methanol, ethanol or similar lower alkyl alcohol, in acidic conditions can also be employed for the iminoether preparation.
  • the iminoether then reacts with compound of formula 5a or 5b towards compound of formula 6b or 6c.
  • the subsequent reaction with compound 5 is effected upon mixing the latter with the highly reactive iminoether of compound 3 in the presence of a suitable solvent.
  • suitable solvents are polar organic solvents.
  • Preferable polar organic solvents are lower alkyl alcohols, such as methanol, ethanol, n-propanol, i-propanol, n-butanol, sec-butanol, iso-butanol.
  • the iminoether is preferably formed in situ. The reaction can take place in temperatures ranging from ambient temperature to heating till the boiling point of the employed solvent.
  • the cyclization reaction of any of the previously described embodiments which leads to the formation of the triazole ring, takes place in temperatures ranging from ambient temperature to heating till the boiling point of the employed solvent.
  • the refluxing conditions are preferable in order to force the dehydration reaction of the amino-alcohol which is formed as an intermediate during the cyclization reaction.
  • the pressure under which the reaction is performed may be atmospheric pressure or higher. To achieve pressures higher than 1 atm suitable equipment readily available in small or industrial scale may be employed.
  • the pressure can either increase as a result of a seal-closed vessel, or by employing some inert gas, such as Argon, to artificially increase the pressure. Increasing pressure results in acceleration of the reaction.
  • the cyclization reaction may be effected by addition of an acid.
  • Preferable acids are inorganic acids, but strong organic acids may be equally effective.
  • Preferable inorganic acids arehydrohalic acids, sulfuric acid, hydrosulfuric acid, nitric acid, phosphoric acid, boric acid, hydrocyanic acid.
  • Preferable organic acids are formic acid, oxalic acid, acetic acid, trifluoroacetic acid, benzoic acid.
  • Another sensitive feature of this reaction is the reaction time. The reaction time is totally depended on the reaction temperature and pressure and it falls into a range that avoids the formation of undesirable and decomposition products.
  • the conversion of the carbamoyl group to cyano group can be easily held in the presence of suitable dehydrating reagents in a suitable solvent.
  • suitable dehydrating reagents which can be employed in the dehydration step are thionyl chloride (SOCl 2 ), phosgene (COCl 2 ), phosphorous pentachloride (PC1 5 ), phosphoryl chloride (POCl 3 ), trifluoromethanosulfonic anhydride [(CF 3 S0 2 ) 2 0], trifluoroacetic anhydride [(CF 3 CO) 2 0], cyanuric chloride, ethyl dichlorophosphate (EtOPOCl 2 ), phosphorus oxides such as phosphorus pentoxide (P 4 0,o), phosphorus trioxide (P 4 O 6 ) or similar oxides, or said formation can be performed in the presence of oxygen.
  • Preferable organic bases are organic amines.
  • Preferable organic amines are methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, diisopropylethylamine (DIPEA), 1.8-diazabicylo(5.4.0)undec-7-ene (DBU), 1.5- diazabicyclo(4.3.0)non-5-ene (DBN), 1.4-diazabicyclo(2.2.2)octane (DABCO) or similar.
  • Preferable inorganic bases are sodium hydroxide, potassium hydroxide or similar hydroxides, sodium carbonate, potassium carbonate or similar carbonates, sodium hydrogen carbonate or similar hydrogen carbonates.
  • the solvent is selected from halogenated solvents such as dichloromethane, chloroform and similar halogenated solvents, amides solvents such as NN'- dimethylformamide, dimethylacetamide or similar amide solvents, ethers such us diethylether, tetrahydrofuran, te -butylmethylether or similar ethers, esters such as ethyl acetate, propyl acetate or similar esters, aliphatic hydrocarbons such as pentane, hexane or similar aliphatic hydrocarbons, aromatic hydrocarbons such as benzene, toluene or similar aromatic hydrocarbons, carboxylic acids such as acetic acid, trifluoroacetic acid or similar carboxylic acids, amines such as trimethylamine, pyridine or similar amines, or mixture thereof.
  • halogenated solvents such as dichloromethane, chloroform and similar halogenated solvents
  • amides solvents such as
  • the reaction contains a base
  • the product of the above reaction may optionally be isolated as a salt.
  • the salt may be formed from the acid generated by the dehydrating agent.
  • the trifluoroacetic anhydride forms the trifluoroacetic acid salt of compound of formula 1.
  • other acids may additionally be used in this step of the process, for the preparation of salts of compound of formula 1.
  • the salt formed in this way may not necessarily be a pharmaceutically acceptable salt.
  • This salt can then be used for the preparation and isolation of compound of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, according to standard synthetic techniques, well established in the field of organic chemistry.
  • steps a and b or a' and b' are performed without isolation of intermediate compound 6.
  • the iminoether of compound 3 reacts with compound of formula 5 to form compound of formula 6 and the reaction mass remains under such conditions, as described above, which lead to the formation of the triazole ring.
  • the conversion of compound of formula 6b or 6c to compound of formula 1 can be effected simultaneously by proper choice of reagents.
  • Reagents which act as dehydrating agents and are also capable of generating acidic conditions are suitable for this purpose.
  • Such reagents are for example thionyl chloride (SOCl 2 ), phosgene (COCl 2 ), phosphorous pentachloride (PC1 5 ), phosphoryl chloride (POCl 3 ), trifluoroacetic anhydride.
  • 1H-NMR 500MHz, DMSO) ⁇ 8.90 (d, 2H), 8.79 (d, 2H), 8.52 (s, 1H), 8.30 (d, 1H), 8.01 (d, 2H).
  • Topiroxostat HC1 salt 10 g are added under stirring to 60ml Na 2 C0 3 saturated solution over a period of 1 hour maintaining pH above 7.
  • the resulting suspension is filtered off, washed with 2x50 ml of cold water and dried at 80 °C under vacuum to afford 7.1 g of Topiroxostat as crystal type II.
  • Topiroxostat 3.0g of Topiroxostat are dissolved in 22.5ml of ⁇ , ⁇ -dimethylformamide and the mixture is heated under stirring at 150 °C for 25min. The obtained suspension is cooled down at room temperature and the precipitated crystals are recovered through filtration. Crystals are washed with cold D.M. water (2x10ml) and dried overnight at 80 °C under vacuum to yield 2.48g of Topiroxostat as crystal type II.

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PCT/EP2016/000343 2015-02-25 2016-02-24 Methods for the preparation of topiroxostat and intermediates thereof WO2016134854A1 (en)

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CN201680023004.9A CN107531677A (zh) 2015-02-25 2016-02-24 用于制备托匹司他及其中间体的方法
JP2017544629A JP6811717B2 (ja) 2015-02-25 2016-02-24 トピロキソスタット及びその中間体の調製のための方法

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Cited By (4)

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CN108250183A (zh) * 2016-12-29 2018-07-06 北京诚济制药有限公司 一种高纯度的托匹司他的制备方法
CN115308347A (zh) * 2022-09-01 2022-11-08 江苏知原药业股份有限公司 一种托吡司特中氮氧化物杂质的分析方法
CN115572747A (zh) * 2022-09-23 2023-01-06 湖南一格制药有限公司 托匹司他的制备方法
CN116396275A (zh) * 2023-03-03 2023-07-07 浙江国邦药业有限公司 一种托匹司他的合成方法

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CN113666909B (zh) * 2020-05-14 2024-07-02 鲁南制药集团股份有限公司 一种托匹司他的制备方法
CN114685451A (zh) * 2020-12-30 2022-07-01 鲁南制药集团股份有限公司 马来酸托匹司他二水合物共晶及其制备方法
CN114685452A (zh) * 2020-12-31 2022-07-01 鲁南制药集团股份有限公司 一种托匹司他-水杨酸-乙酸三元共晶
CN115477638A (zh) * 2022-10-09 2022-12-16 浙江神洲药业有限公司 一种托匹司他的制备方法

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108250183A (zh) * 2016-12-29 2018-07-06 北京诚济制药有限公司 一种高纯度的托匹司他的制备方法
CN115308347A (zh) * 2022-09-01 2022-11-08 江苏知原药业股份有限公司 一种托吡司特中氮氧化物杂质的分析方法
CN115308347B (zh) * 2022-09-01 2023-09-08 江苏知原药业股份有限公司 一种托吡司特中氮氧化物杂质的分析方法
CN115572747A (zh) * 2022-09-23 2023-01-06 湖南一格制药有限公司 托匹司他的制备方法
CN115572747B (zh) * 2022-09-23 2023-05-05 湖南一格制药有限公司 托匹司他的制备方法
CN116396275A (zh) * 2023-03-03 2023-07-07 浙江国邦药业有限公司 一种托匹司他的合成方法
CN116396275B (zh) * 2023-03-03 2025-05-13 浙江国邦药业有限公司 一种托匹司他的合成方法

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