JP2018507858A - Process for the preparation of topiroxostat and its intermediates - Google Patents

Abstract

The present invention relates to a novel process for the preparation of topiroxostat via a novel intermediate, including a novel process for the formation of a triazole ring and for the cyanation reaction of a pyridyl ring. [Selection figure] None

Description

  The present invention relates to a novel process for the preparation of topiroxostat via a novel intermediate.

  Topiroxostat of Formula 1 belongs to a large family of novel 1,2,4-triazole compounds and is characterized by high xanthine oxidase inhibitory activity. This is useful as a therapeutic agent for hyperuricemia caused by increased production of uric acid and gout caused by hyperuricemia. Topiroxostat shows an effective reduction in serum uric acid levels in hyperuricemia patients with or without gout.

Topiroxostat or FYX-051 is available from Fuji Yakuhin Co. Ltd .. First, and its synthesis is described in EP 147065B. In this first synthesis of topiroxostat 1, the introduction of a cyano group onto the pyridyl ring takes place in the first step prior to the condensation reaction.

Several years later, a new method for the preparation of Formula 1 topiroxostat was published. This new method described in EP 1650204A involves the introduction of a cyano group after formation of the triazole ring.

WO2014017516 presents another route for the preparation of topiroxostat of formula 1 in which the introduction of a cyano group on the pyridyl ring is carried out prior to the formation of the triazole ring. The

In 2008, Yamamoto et al.-Tet. Lett. 49, 4369-4371, 2008 described a simple method for a direct cyanation reaction using zinc cyanide as a cyanation reaction reagent. This is the application of this new method to the preparation of topiroxostat, avoiding the use of protecting groups and replacing TMSCN with Zn (CN) ₂ .

CN103724329B described an alternative method for the preparation of topiroxostat as shown in the following scheme.

  The above method has a major drawback. EP1471065, EP1650204, WO20141751616 and Yamamoto use cyanide species to introduce a cyano group into the pyridyl moiety. These types of reagents must be handled with special care because they hydrolyze to form hydrogen cyanide, a highly toxic chemical compound. On the other hand, CN103724329B has a number of steps, uses expensive starting materials, and has a disadvantage of low yield. In addition, the method involves the use of cyanuric chloride, a toxic reagent. Therefore, it is really difficult to develop a new “green” method that avoids the use of cyanide species, yields higher yields, and is less intrusive to ring environment problems.

  The present invention relates to topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate thereof, through a novel intermediate that avoids the use of hazardous reagents or tedious redundant processes. , New methods for the preparation of solvates or polymorphs are disclosed.

The present invention relates to topiroxostat of formula 1 or any of its for the cyanidation reaction of pyridyl ring avoiding the use of cyanide species such as NaCN, HCN, KCN, TSMCN, CuCN, Zn (CN) ₂ Disclosed are new methods for the preparation of pharmaceutically acceptable salts, hydrates, solvates or polymorphs. This new method results in the preparation of topiroxstat using a new scheme for the introduction of cyano groups on pyridyl rings using cheaper and safer reagents.

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, which process:
a) reacting a compound of formula 3 with a compound of formula 5 in the presence of a base to form a compound of formula 6
[Wherein R ₁ and R ₂ are each independently selected from hydrogen or a carbamoyl group, provided that R ₁ and R ₂ are not the same];
b) converting the compound of formula 6 to the compound of formula 7
[Wherein R ₁ and R ₂ are as defined in step (a) above];
c) converting the compound of formula 7 to topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
[Wherein R ₁ and R ₂ are as defined in step (a)]
including.

As disclosed above, R ₁ and R ₂ represent hydrogen or a carbamoyl group throughout the present invention unless otherwise specified.

Another embodiment of this invention is a compound of formula 6 wherein R ₁ and R ₂ are as defined above, topiroxostat of formula 1 or any pharmaceutically acceptable thereof Direct conversion to salt, hydrate, solvate or polymorph.

  A further embodiment of the invention is the introduction of a cyano group onto the pyridyl ring without the use of a cyanide species. The cyanidation reaction of the pyridyl group is carried out by introducing the carbamoyl group and then directly converting it to the cyano group according to the present invention.

Another embodiment of the invention discloses the conversion of the R ₁ or R ₂ group to a cyano group at any step of the process when neither the R ₁ group nor the R ₂ group is hydrogen.

  The present invention discloses a novel process for the production of topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof via a novel intermediate. .

  The present invention avoids the use of cyanide species, poses major environmental problems and utilizes a short and efficient synthesis procedure, or toloxostat of formula 1, or any pharmaceutically acceptable salt thereof, A novel method for the preparation of hydrates, solvates or polymorphs is disclosed. This new method for topyroxostat uses a different method for the cyanation reaction on the pyridyl ring, characterized by the use of a group that is readily convertible to a 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, which comprises:
a) A compound of formula 3a [wherein R ₁ is a carbamoyl group] and a compound of formula 5b [wherein R ₂ is hydrogen] are reacted in the presence of a base to give a compound of formula 6b [formula Wherein R ₁ is a carbamoyl group and R ₂ is hydrogen];
Or a ′) a compound of formula 3b [R ₁ is hydrogen] and a compound of formula 5a [R ₂ is a carbamoyl group] in the presence of a base to give a compound of formula 6c [wherein R ₁ Is hydrogen and R ₂ is a carbamoyl group];
b) a compound of formula 6b obtained in step a) [wherein R ₁ is a carbamoyl group and R ₂ is hydrogen], a compound of formula 7 [wherein R ₁ is a carbamoyl group, R ₂ is hydrogen]
Or b ′) the compound of formula 6c obtained in step a ′) [R ₁ is hydrogen and R ₂ is a carbamoyl group], or the compound of formula 7 [R ₁ is hydrogen and R ₂ is carbamoyl. Converting to a radical];
c) converting the compound of formula 7 obtained in step (b) or (b ′) to topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. Converting.

The present invention provides novel intermediates of formulas 6 and 7. These novel intermediates can be used in the methods disclosed in the present invention depending on the reagents used in the course of the method and as salts. Thus, compounds of formula 6 and 7 can be isolated as salts when an acid is used in step a or b.
The present invention provides a process for preparing novel intermediates of formula 6 from compounds of formulas 3 and 5, as described above.

  The present invention provides a process for preparing novel intermediates of formula 7 from compounds of formula 6, as described above. The method can further comprise the preparation of a compound of formula 6 from compounds of formulas 3 and 5, as described above.

  Another embodiment of the present invention is step (b) or (b '), wherein (c) can be carried out without isolating any intermediate.

Another embodiment of the present invention is a compound of formula 6b or 6c prepared as described above, of topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate thereof or Conversion to polymorphism. The formation of the triazole ring and the conversion of the carbamoyl group can be carried out simultaneously by the method described in the present invention.

  A particular embodiment of the present application is that the introduction of the carbamoyl group can be carried out at any step of the above method.

  Another embodiment of the present invention is that the conversion of the carbamoyl group to a cyano group can be carried out at any step of the novel process.

A further embodiment of the invention is the introduction of a carbamoyl group onto the pyridyl ring of 4-cyano-pyridine to form a compound of formula 3b.

One embodiment of the present invention is the introduction of a carbamoyl group onto the pyridyl ring of isonicotinohydrazide to form a compound of formula 5a wherein R ₂ is a carbamoyl group.

  All the improvements of the above method over the prior art method are the introduction of the carbamoyl group onto the pyridyl group and its conversion to the cyano group by using inexpensive starting materials in the absence of highly toxic reagents. is there. At the same time, the present invention provides a rapid and efficient method wherein steps a and b, or steps a 'and b', can be carried out preferably without isolation of intermediates.

The carbamoylation step can be accomplished using formamide (HCONH ₂ ) in the presence of an acid or radical initiator. Carbamoylation is carried out in the presence of an inorganic acid such as nitric acid, sulfuric acid or a similar inorganic acid, or an organic acid such as formic acid, acetic acid or a similar organic acid. Introduction of a carbamoyl group can be achieved in the presence of a radical initiator such as CAN (ammonium cerium nitrate) or similar reagents.

  The carbamoylation reaction is derived from TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), NHPI (N-hydroxyphthalimide) or similar reagents, TEMPO [(2,2 , 6,6-tetramethylpiperidin-1-yl) oxyl], PINO (phthalimido-N-oxyl) or similar reagents can be catalyzed by hydroxyl radicals.

  In any of the above embodiments, in step (a) or (a '), 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 can be, for example, methanol, ethanol or similar lower alkyl alcohol, and is easily converted to the corresponding alkoxide in the presence of a base. Alternatively, alcohols such as methanol, ethanol or similar lower alkyl alcohols can also be used for the preparation of imino ethers under acidic conditions. The imino ether then reacts with the compound of formula 5a or 5b to give the compound of formula 6b or 6c.

  Subsequent reaction with compound 5 is carried out by mixing the compound with the highly reactive imino ether of compound 3 in the presence of a suitable solvent. A suitable solvent is a polar organic solvent. Preferred polar organic solvents are lower alkyl alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butanol, sec-butanol, iso-butanol. The imino ether is preferably formed in situ. The reaction can take place in a temperature range from room temperature to the boiling point of the solvent used.

  In any of the above embodiments, the cyclization reaction results in the formation of a triazole ring and is performed in a temperature range from room temperature to the boiling point of the solvent used. Reflux conditions are preferred in order to force dehydration of the amino-alcohol formed as an intermediate during the cyclization reaction.

  The pressure at which the reaction is carried out can be at or above atmospheric pressure. Appropriate equipment readily available on a small or industrial scale can be used to achieve pressures higher than 1 atmosphere. The pressure can be raised by closing the container in an airtight manner or artificially increased by using some inert gas such as argon. Increasing the pressure accelerates the reaction.

  Alternatively, the cyclization reaction can be carried out by addition of an acid. Preferred acids are inorganic acids, but strong organic acids are equally effective. Preferred inorganic acids are hydrohalic acid, sulfuric acid, hydrosulfuric acid, nitric acid, phosphoric acid, boric acid, and hydrocyanic acid. Preferred 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 depends entirely on the reaction temperature and pressure and falls within a range that avoids the formation of undesirable decomposition products.

In all of the above embodiments, the conversion of the carbamoyl group to the cyano group is easily maintained in the presence of a suitable dehydrating reagent in a suitable solvent. Suitable dehydrating reagents that can be used in the dehydration step include thionyl chloride (SOCl ₂ ), phosgene (COCl ₂ ), phosphorus pentachloride (PCl ₅ ), phosphoryl chloride (POCl ₃ ), trifluoromethanosulfonic anhydride [( CF ₃ SO ₂ ) ₂ O], trifluoroacetic anhydride [(CF ₃ CO) ₂ O], cyanuric chloride, ethyl dichlorophosphate (EtOPOCl ₂ ), phosphorus pentoxide (P ₄ O ₁₀ ), phosphorus trioxide (P ₄₎ Phosphorus oxide such as O ₆ ) or similar oxides or the formation can be carried out in the presence of oxygen.

  This reaction is carried out in the presence of a suitable base selected from organic or inorganic bases. A preferred organic base is an organic amine. Preferred organic amines are methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, diisopropylethylamine (DIPEA), 1.8-diazabicyclo (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 the like. Preferred inorganic bases are sodium hydroxide, potassium hydroxide or similar hydroxide, sodium carbonate, potassium carbonate or similar carbonate, sodium bicarbonate or similar hydrogen carbonate.

  Solvents for the above steps are halogenated solvents such as dichloromethane, chloroform and similar halogenated solvents, amide solvents such as N, N′-dimethylformamide, dimethylacetamide or similar amide solvents, diethyl ether, tetrahydrofuran, and tert-butylmethyl. Ethers such as ether or similar ethers, esters such as ethyl acetate, propyl acetate or similar esters, aliphatic hydrocarbons such as pentane, hexane or similar aliphatic hydrocarbons, benzene, toluene or similar aromatic hydrocarbons, etc. Selected from aromatic hydrocarbons, carboxylic acids such as acetic acid, trifluoroacetic acid or similar carboxylic acids, amines such as trimethylamine, pyridine or similar amines, or mixtures thereof.

  Although the reactant contains a base, the product of the above reaction may optionally be isolated as a salt. This salt may be formed from an acid produced by a dehydrating agent. For example, trifluoroacetic anhydride forms the trifluoroacetate salt of the compound of Formula 1. Alternatively, other acids may additionally be used in this step of the process for the preparation of salts of the compound of formula 1. The salt thus formed does not necessarily have to be a pharmaceutically acceptable salt.

  This salt is then prepared and isolated according to standard synthetic techniques established in the field of organic chemistry, of the compound of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. Can be used for.

  In a preferred embodiment, steps a and b or steps a 'and b' are performed without isolating intermediate compound 6. According to this embodiment, the imino ether of compound 3 reacts with the compound of formula 5 to form the compound of formula 6, and as described above, the reaction mass is maintained under such conditions, which is a triazole ring. Resulting in the formation of.

In another embodiment described above, the conversion of a compound of formula 6b or 6c to a compound of formula 1 can be performed simultaneously by appropriate selection of reagents.
Reagents that act as dehydrating agents and can produce acidic conditions are suitable for this purpose. Such reagents are, for example, thionyl chloride (SOCl ₂ ), phosgene (COCl ₂ ), phosphorus pentachloride (PCl ₅ ), phosphoryl chloride (POCl ₃ ), trifluoroacetic anhydride.

  The polymorph of the compound of formula 1 was characterized according to the patent application WO201417515.

Example 1
Preparation of 2-carbamoyl-4-cyano-pyridine (3a) 3 L 4 neck r. Equipped with magnetic stirrer, thermometer and 500 mL addition funnel. b. A flask is charged with 100 g of 4-cyano-pyridine, followed by 800 ml of acetonitrile. Sulfuric acid (20 ml) is added dropwise at room temperature. The resulting suspension is heated to 60 ° C. 60 ml of D.I. M.M. A solution of formamide (200 ml) in water is charged to the addition funnel and added at 60 ° C. over 10 minutes. The resulting clear solution is heated to 70 ° C. 328 g of ammonium peroxydisulfate is added to the solution in small portions to maintain the temperature at 70-75 ° C. After the addition is complete, the reaction mixture is stirred at 75 ° C. for about 1 hour. The reaction was monitored by TLC and after completion, 1 L of D.P. M.M. Add water. The solvent is distilled off under reduced pressure. The warm suspension is filtered off. 500 mL of the D. wet cake. M.M. Wash with water and dry under reduced pressure to give 121 g of 2-carbamoyl-4-cyano-pyridine as a white solid.

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

Example 2
Preparation of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) picolinamide (7) To a 2 L hydrogenator equipped with a magnetic bar was added 115 g of 2- Charge carbamoyl-4-cyano-pyridine (3a) followed by 1150 mL of methanol. 26.6 g of 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 acid hydrazide (5b) is added. The resulting suspension is heated to 90 ° C. under pressure (4 bar) for 2 hours. The reaction is heated to 100 ° C. with stirring and pressure (4 bar) for 6-10 hours. The suspension was filtered off and the wet cake was washed with 200 ml of methanol and dried under reduced pressure to give 121 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazole- 3-yl) picolinamide 7 is obtained.
The bar filtrate is evaporated to dryness to give 185 g of crude product. The crude product is dissolved in 555 ml DM water. The resulting suspension is heated at 80 ° C. for 2 hours and cooled at room temperature. The suspension is filtered off. The wet cake was washed with 200 ml of methanol and dried under reduced pressure to give an additional amount of 78 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) picolinamide (7) is obtained as a white solid.

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

Example 3
Preparation of topiroxostat 250 ml three-neck r.b. with bar magnetic bar and thermometer b. A flask is charged with 10.0 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) picolinamide (7) dissolved in 60 ml of THF. 7.86 ml of triethylamine is added. The reaction mixture is cooled to 0 ° C. and 6.95 ml of trifluoroacetic anhydride (TFAA) is added dropwise. After the addition of TFAA, the reaction mixture is left under stirring at room temperature. The reaction is monitored by TLC and after completion, the solvent is evaporated and the crude API TFA salt is isolated as a yellow solid. This salt is dissolved in 50 ml of MeOH and heated at 70 ° C. for 1 hour. The suspension is cooled to room temperature and filtered off. The wet cake was washed with 200 ml of chilled methanol and dried under reduced pressure to yield 7.6 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) A picolinonitrile TFA salt is obtained.

  1H-NMR (500 MHz, 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 M.M. Dissolve in 71 ml of a mixture of water / 2-butanol (9: 1) (pH = 4) and add 7.2 g of K ₂ CO _{3 in} portions (pH = 10) at room temperature. 12.9 ml HCl (6N) (pH = 7) is added dropwise at room temperature. The reaction mixture is left under stirring for 5 hours. The reaction is monitored by TLC, and upon completion, a light yellow solid is filtered off, washed with 2 × 50 ml of cold water and dried under reduced pressure at 80 ° C. to give topiroxostat as crystalline Form I.

1H-NMR (500 MHz, DMSO) δ 8.90 (d, 2H), 8.79 (d, 2H), 8.52 (s, 1H), 8.30 (d, 1H), 8.01 (d , 2H).
13C-NMR (125 MHz, DMSO) δ 152.2, 150.7, 133.6, 125.1, 123.7, 120.2, 117.2.

Example 4
Preparation of Topiroxostat 250 ml three-neck r.g. with magnetic bar and thermometer b. A flask is charged with 10.0 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) picolinamide (7) dissolved in 60 ml of THF. Add 27 ml of triethylamine. The reaction mixture is cooled to 0 ° C. and 14 ml of trifluoroacetic anhydride (TFAA) is added dropwise. After the addition of TFAA, the reaction mixture is left under stirring at room temperature for 1 hour. The reaction is monitored by TLC and upon completion, the solvent is evaporated to form the crude API. The crude solid is dissolved in 50 ml DCM and heated at 40 ° C. for 1 hour. The suspension is cooled to room temperature and filtered off. The wet cake is washed with 10 ml of DCM and dried under reduced pressure to give 6.5 g of topiroxostat as crystalline Form I.

1H-NMR (500 MHz, DMSO) δ 8.90 (d, 2H), 8.79 (d, 2H), 8.52 (s, 1H), 8.30 (d, 1H), 8.01 (d , 2H).
13C-NMR (125 MHz, DMSO) δ 152.2, 150.7, 133.6, 125.1, 123.7, 120.2, 117.2.

Example 5
Preparation of topiroxostat 250 ml three-neck r.g. equipped with magnetic bar, water condenser and thermometer r. b. A flask is charged with 10.0 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) picolinamide (7) dissolved in 50 ml of toluene. The suspension obtained above is heated to 100 ° C. and 7.86 ml of phosphorus oxychloride is added. The reaction mixture is further heated at 105 ° C. for 5-6 hours. The reaction is monitored by TLC and after completion, the solvent is evaporated to form 16.4 g of crude product (API HCl salt). Dissolve the crude solid in 50 ml of toluene and evaporate to remove excess POCl ₃ to give 10 g of crude mixture (API HCl salt).

  1H-NMR (500 MHz, DMSO) δ 9.07 (d, 2H), 8.95 (d, 1H), 8.67 (s, 1H), 8.63 (d, 2H), 8.41 (d , 1H).

10 g of topiroxostat HCl salt is added to 60 ml of saturated Na ₂ CO ₃ solution over 1 hour under stirring to maintain the pH above 7. The resulting suspension is filtered off, washed with 2 × 50 ml of cold water and dried under reduced pressure at 80 ° C. to give 7.1 g of topiroxostat as crystalline Form II.

Example 6
Preparation of topiroxostat 3.0 g of topiroxostat is dissolved in 22.5 ml of N, N-dimethylformamide and the mixture is heated under stirring at 150 ° C. for 25 minutes. The resulting suspension is cooled to room temperature and the precipitated crystals are collected by filtration. The crystals were cooled. M.M. Wash with water (2 × 10 ml) and dry under reduced pressure at 80 ° C. overnight to obtain 2.48 g of topiroxostat as crystalline Form II.

Claims (17)

A process for the preparation of topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate, solvate and polymorph thereof:
a) reacting a compound of formula 3 with a compound of formula 5 in the presence of a base to form a compound of formula 6
[Wherein R ₁ and R ₂ are each independently selected from hydrogen or a carbamoyl group, provided that R ₁ and R ₂ are not the same];
b) converting the compound of formula 6 to the compound of formula 7
[Wherein R ₁ and R ₂ are as defined above];
c) Converting the compound of formula 7 to topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate and polymorph thereof.
[Wherein R ₁ and R ₂ are as defined above]
Including methods. A method for the preparation of a compound of formula 6 wherein R ₁ and R ₂ are independently selected from hydrogen or a carbamoyl group, provided that R ₁ and R ₂ are not the same, the compound of formula 3 and the compound of formula 5 A process comprising reacting with a compound, wherein R ₁ and R ₂ are defined as above. A process for the preparation of a compound of formula 7, wherein R ₁ and R ₂ are as defined in claim 1, comprising the conversion of a compound of formula 6 to a compound of formula 7, wherein R ₁ and R _{2. A} method, wherein ₂ is as defined in claim 1.   Further reacting the compound of formula 3 with the compound of formula 5 in the presence of a base to form a compound of formula 6 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. 4. The method of claim 3, comprising.   5. A process according to claim 1 or 4 wherein steps a and b or a 'and b' are performed without isolating the compound of formula 6. Formula 1
A process for the preparation of or of any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof:
a) reacting a compound of formula 3 with a compound of formula 5 in the presence of a base to form a compound of formula 6
[Wherein R ₁ and R ₂ are defined as in claim 1];
b) converting the compound of formula 6 into topiroxstat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
[Wherein R ₁ and R ₂ are defined as above]
Including methods.   A process for the preparation of topiroxostat comprising the conversion of a compound of formula 7 to topiroxostat in the presence of a dehydrating agent.   A compound of formula 1 is isolated as a salt from the reaction of step c and then converted to the free base, pharmaceutically acceptable salt, hydrate, solvate or polymorph of the compound of formula 1 Item 8. The method according to Item 1, 4, 5, 6, or 7. R ₁ is a carbamoyl group, R ₂ is hydrogen, the compound of formula 3 is a compound of formula 3a, the compound of formula 5 is a compound of formula 5b, and the compound of formula 6 is a compound of formula 6b A method according to any one of claims 1 to 8. R ₁ is hydrogen, R ₂ is a carbamoyl group, the compound of formula 3 is a compound of formula 3b, the compound of formula 5 is a compound of formula 5a, and the compound of formula 6 is a compound of formula 6c 10. A method according to any one of claims 1 to 9.   Providing a non-pharmaceutically acceptable salt of the compound of formula 1, and to the compound of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof A process for the purification of a compound of formula 1 comprising the conversion of   Use of a compound of formula 6b for the production of topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.   Use of a compound of formula 6c for the production of topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. R ₁ and R ₂ are independently selected from hydrogen or a carbamoyl group, provided that R ₁ and R ₂ are not the same, topiroxstat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvent thereof Use of a compound of formula 7 for the production of a solvate or polymorph.   Compound of formula 6b.   Compound of formula 6c. A compound of formula 7 wherein R ₁ and R ₂ are defined as in claim 1.