METHODS FOR THE PREPARATION OF TOPIROXOSTAT AND

INTERMEDIATES THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel preparation methods for Topiroxostat through novel intermediates.

BACKGROUND OF THE INVENTION

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.

A few years later, a new method for the preparation of Topiroxostat of formula 1 was published. The new method described in EP1650204A comprises the introduction of the cyano group after the formation of the triazole ring.

In WO2014017516, an alternative route for the preparation of Topiroxostat of formula 1 was presented, wherein the introduction of the cyano group on the pyridyl ring is performed prior to the formation of the triazole ring.

In 2008, Yamamoto et al. - Tet. Lett. 49, 4369-4371, 2008 - described a convenient method for the direct cyanation using zinc cyanide as a cyanation reagent. They applied this new method in the preparation of Topiroxostat avoiding the use of any protecting groups and replacing TMSCN with Zn(CN)2.

CN103724329B described an alternative process for the preparation of Topiroxostat, as shown in the next scheme.

The above mentioned processes suffer from major drawbacks. EP 1471065, EP 1650204, WO2014017516 and Yamamoto use cyanide species for the introduction of the cyano group on the pyridyl moiety. Such kind of reagents must be treated with special care since they hydrolyze to yield hydrogen cyanide, an extremely poisonous chemical compound. On the other hand CN103724329B, consists of many steps, uses expensive starting materials and suffers from low yields. Additionally, it employs the use of cyanuric chloride, which is a toxic reagent. Thus, it is really challenging to develop a new 'green' process that avoids the use of cyanide species, leading to higher yields and is industrially applicable having less environmental concerns.

SUMMARY OF THE INVENTION

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

wherein Ri and R2 are each independently selected from hydrogen or a carbamoyl group, with the proviso that R| and R2 are not the same;

b) converting compound of formula 6, to compound of formula 7

7

wherein R| and R2 are as defined above in step (a);

c) converting compound of formula 7, to Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof

wherein R{ and R2 are as defined in step (a).

As disclosed above, Ri and R2 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 R2 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 R2 group, when either of them is not hydrogen, to cyano group in any step of the process.

DETAILED DESCRIPTION OF THE INVENTION

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 R2 is hydrogen, in the presence of a base to form compound of formula 6b, wherein Ri is a carbamoyl group and R2 is hydrogen ;

or

a') reacting compound of formula 3b, wherein R] is hydrogen, with compound of formula 5a, wherein R2 is a carbamoyl group, in the presence of a base to form compound of formula 6c, wherein R] is hydrogen and R2 is a carbamoyl group;

converting compound of formula 6b from step a), wherein Ri is a carbamoyl group and R2 is a hydrogen, to compound of formula 7, wherein R[ is a carbamoyl group and

6b

or

b') converting compound of formula 6c from step a'), wherein R is a hydrogen and R2 is a carbamoyl group, to compound of formula 7, wherein R! is a hydrogen and R2 is a carbamoyl group;

c) converting compound of formula 7, prepared either from step (b) or (V), , to Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof

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.

Another embodiment of the present invention is that 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 R2 is a carbamoyl group.

5a

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, at the same time, 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 (HCONH2) 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. 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.

In 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. Alternatively, 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.

Alternatively, 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.

In all previously described embodiments, 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 (SOCl2), phosgene (COCl2), phosphorous pentachloride (PC15), phosphoryl chloride (POCl3), trifluoromethanosulfonic anhydride [(CF3S02)20], trifluoroacetic anhydride [(CF3CO)20], cyanuric chloride, ethyl dichlorophosphate (EtOPOCl2), phosphorus oxides such as phosphorus pentoxide (P40,o), phosphorus trioxide (P4O6) or similar oxides, or said formation can be performed in the presence of oxygen.

This reaction takes place in the presence of a suitable base selected from organic or inorganic bases. 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, of the above mentioned step, 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.

Although 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. For example, the trifluoroacetic anhydride forms the trifluoroacetic acid salt of compound of formula 1. Alternatively, 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.

In a preferred embodiment, steps a and b or a' and b' are performed without isolation of intermediate compound 6. According to this embodiment, 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.

In another embodiment, described previously, 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 (SOCl2), phosgene (COCl2), phosphorous pentachloride (PC15), phosphoryl chloride (POCl3), trifluoroacetic anhydride.

EXAMPLES

The polymorphs of compound of formula 1 were characterized according to patent application WO2014017515.

Example 1

Preparation of 2-carbamoyl-4-cyano-pyridine 3a

A 3 L 4-necked r.b. flask equipped with a magnetic stirrer, thermometer and a 500 mL addition funnel is charged with 100 g 4-cyano-pyridine followed by 800 ml acetonitrile. Sulfuric acid (20 ml) is added dropwise at room temperature. The resulting suspension is heated at 60 °C. A solution of Formamide (200 ml) in 60 ml D.M. water is charged to the addition funnel and added over a period of 10 min. at 60 °C. The resulting clear solution is heated at 70 °C. 328 g Ammonium peroxydisulfate are added to the solution in portions maintaining the temperature between 70-75 °C. After the completion of the addition, the reaction mixture is stirred at 75 °C for approximately one hour. The reaction is monitored with TLC and after completion 1 L of D.M. water is added. Solvents are distilled off under vacuum. The warm suspension is filtered off. The wet cake is washed with 500 mL D.M. water and dried under vacuum to give 12 lg of 2-carbamoyl-4-cyano-pyridine as a white solid.

1H-NMR (500MHz, DMSO) δ 8.88 (d, 1H), 8.33 (s, 1H), 8.27 (br, 1H), 8.06 (d, 1 H), 7.88 (br, 1H)

Example 2

Preparation of 4-(5-(pyridin-4-yl)-l H-l,2,4-triazol-3-yl)picolinamide 7

A 2 L hydrogenator equipped with a magnetic bar, is charged with 1 15 g 2-carbamoyl-4-cyano-pyridine (3a) followed by 1 150 mL methanol. 26.6 g sodium methoxide are added in portions at room temperature. The suspension is left under stirring for 2 hours to form the corresponding imino ether. After consumption of the starting material 106.9 g of isonicotinic hydrazide (5b) are added. The resulting suspension is heated at 90 °C under pressure (4 bar) for 2 hours. The reaction is heated at 100 °C under stirring and pressure (4 bar) for 6-10 hours. The suspension is filtered off, the wet cake is washed with 200 ml methanol and dried under vacuum to afford 121 g of 4-(5-(pyridin-4-yl)-l H-l ,2,4-triazol-3-yl)picolinamide 7.

Filtrate is evaporated to dryness, to afford 185 g crude product. The crude product is dissolved in 555 ml DM water. The resulting suspension is heated at 80 °C for 2 h and cooled down at room temperature. The suspension is filtered off. Wet cake is washed with 200 ml methanol and dried under vacuum to afford an additional amount of 78 g of 4-(5-(pyridin-4-yl)-lH-l ,2,4-triazol-3-yl)picolinamide 7 as a white solid.

1H-NMR (500MHz, DMSO) δ 8.64 (s, 1H), 8.55 (d, 1 H), 8.51 (d, 2H), 8.1 (d, 2H), 7.96 (d, 2H), 7.59 (br, 1 H).

Example 3

Preparation of Topiroxostat

A 250ml 3-necked r.b. flask equipped with a magnetic bar and a thermometer is charged with lO.Og of 4-(5-(pyridin-4-yl)-lH-l,2,4-triazol-3-yl)picolinamide (7) dissolved in 60ml of THF. 7.86ml of Triethylamine are added. The reaction mixture is cooled down at 0 °C and 6.95ml of Tnfluoroacetic anhydride (TFAA) are added dropwise. After the addition of TFAA the reaction mixture is left under stirring at room temperature. The reaction is monitored with TLC and after completion solvents are evaporated and crude API TFA salt is isolated as a yellow solid. The salt is dissolved in 50 ml MeOH and heated at 70 °C for 1 h. Suspension is cooled down at room temperature and filtered off. Wet cake is washed with 200 ml chilled methanol and dried under vacuum to afford 7.6 g of 4-(5-(pyridin-4-yl)-lH-l,2,4-triazol-3-yl)picolinitrile TFA salt.

1H-NMR (500MHz, DMSO) δ 8.94 (d, 1H), 8.89 (d, 2H), 8.54 (s, 1H), 8.31 (d, 1H), 8.19 (d, 2H).

7.6 g of Topiroxostat TFA salt are dissolved in 71 ml mixture of D.M. water/2-butanol (9: 1) (pH=4) and 7.2 g of K2C03 are added in portions at room temperature (pH=10). 12.9 ml of HC1 (6N) (pH=7) are dropwise at room temperature. The reaction mixture is left under stirring for 5 hours. The reaction is monitored with TLC and after completion the yellow pale solid is filtered off, washed with 2x50 ml of cold water and dried at 80 °C under vacuum to afford Topiroxostat as crystal type I.

1H-NMR (500MHz, DMSO) δ 8.90 (d, 2H), 8.79 (d, 2H), 8.52 (s, 1H), 8.30 (d, 1H), 8.01 (d, 2H).

13C-NMR (125MHz, DMSO) δ 152.2, 150.7, 133.6, 125.1, 123.7, 120.2, 1 17.2.

Example 4

Preparation of Topiroxostat

A 250ml 3-necked r.b. flask equipped with a magnetic bar and a thermometer is charged with lO.Og of 4-(5-(pyridin-4-yl)-lH-l ,2,4-triazol-3-yl)picolinamide (7) dissolved in 60ml of THF. 27 ml of Triethylamine are added. The reaction mixture is cooled down at 0 °C and 14 ml of Trifluoroacetic anhydride (TFAA) are added dropwise. After the addition of TFAA the reaction mixture is left under stirring at room temperature for 1 hour. The reaction is monitored with TLC and after completion solvents are evaporated and crude API is formed. Above mentioned crude solid is dissolved in 50 ml DCM and heated at 40 °C for 1 h. Suspension is cooled down at room temperature and filtered off. Wet cake is washed with 10 ml DCM and dried under vacuum to afford 6.5 g of Topiroxostat as crystal type I.

1H-NMR (500MHz, DMSO) 5 8.90 (d, 2H), 8.79 (d, 2H), 8.52 (s, 1H), 8.30 (d, 1H), 8.01(d, 2H).

13C-NMR (125MHz, DMSO) δ 152.2, 150.7, 133.6, 125.1, 123.7, 120.2, 1 17.2.

Example 5

Preparation of Topiroxostat

A 250ml 3-necked r.b. flask equipped with a magnetic bar, a water condenser and a thermometer is charged with 10. Og of 4-(5-(pyridin-4-yl)-lH-l,2,4-triazol-3-yl)picolinamide (7) dissolved in 50 ml of Toluene. Above resulting suspension is heated an 100 °C and 7.86ml of Phosphorus oxychloride are added. The reaction mixture is further heated at 105 °C for 5-6 hours. The reaction is monitored with TLC and after completion solvents are evaporated and 16.4 g crude product (API HC1 salt) is formed. Above mentioned crude solid is dissolved in 50 ml Toluene and evaporated to removed excess of POCl3 and afforded 10 g of crude mixture (API HC1 salt).

1H-NMR (500MHz, DMSO) δ 9.07 (d, 2H), 8.95 (d, 1H), 8.67 (s, 1H), 8.63 (d, 2H), 8.4 l(d, 1H).

10 g of Topiroxostat HC1 salt are added under stirring to 60ml Na2C03 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.

Example 6

Preparation of Topiroxostat

3.0g of Topiroxostat are dissolved in 22.5ml of Ν,Ν-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.

CLAIMS

1) A process for the preparation of Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate and 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

wherein Rt and R2 are each independently selected from hydrogen or a carbamoyl group, with the proviso that R| and R2 are not the same; b) converting compound of formula 6 to compound of formula 7

6 7

wherein Ri and R2 are as defined above;

converting compound of formula 7, to Topiroxostat of formula 1 or pharmaceutically acceptable salt, hydrate, solvate and polymorph thereof

wherein R, and R2 are as defined above.

2) A process for the preparation of compound of formula 6, wherein R, and R2 are independently selected from hydrogen or carbamoyl group, with the proviso that R, and R-2 are not the same, comprising reacting compound of formula 3, with compound of formula 5 wherein R, and R2 are defined as above.

3) A process for the preparation of compound of formula 7, wherein Ri and R2 are as defined in claim 1 , comprising conversion of compound of formula 6 to compound of formula 7, wherein R, and R2 are as defined in claim 1.

4) A process according to claim 3, further comprising reacting compound of formula 3 with compound of formula 5 in the presence of a base, to form compound of formula 6 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

5) A process according to claims 1 or 4, wherein steps a and b or a' and b' are performed without isolation of compound of formula 6.

6) A 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

wherein R| and R2 are defined as in claim 1 ;

b) converting compound of formula 6, to Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof

wherein Ri and R2 are defined as above.

7) A process for the preparation of Topiroxostat, comprising the conversion of compound of formula 7 to Topiroxostat in the presence of a dehydrating agent.

8) A process, according to claims 1, 4, 5, 6 or 7, wherein compound of formula 1 is isolated as a salt from the reaction of step c and is subsequently converted to the free base, pharmaceutically acceptable salt, hydrate, solvate or polymorph of compound of formula 1.

9) A process according to any preceeding claim, wherein Ri is carbamoyl group and R2 is hydrogen and compound of formula 3 is compound of formula 3a, compound of formula 5 is compound of formula 5b and compound of formula 6 is compound of formula 6b.

10) A process according to any preceeding claim, wherein R is hydrogen and R2 is carbamoyl group andcompound of formula 3 is compound of formula 3b, compound of formula 5 is compound of formula 5a and compound of formula 6 is compound of formula 6c.

1 1) A process for the purification of compound of formula 1 , comprising providing a non-pharmaceutically acceptable salt of compound of formula 1 and conversion of it to compound of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

12) Use of compound of formula 6b for the production of Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

13) Use of compound of formula 6c for the production of Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

14) Use of compound of formula 7, wherein R| and R2 are independently selected from hydrogen or a carbamoyl group with the proviso that R| and R2 are not the same, for the production of Topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

15) Compound of formula 6b.

16) Compound of formula 6c.

17) Compound of formula 7, wherein R, and R2 are defined as in claim 1.