JP6811717B2 - Methods for the preparation of topiroxostat and its intermediates - Google Patents

Description

The present invention relates to a novel method for preparing 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. It 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. Ltd. First developed by, its synthesis is described in EP1471065B. In this initial synthesis of topiroxostat 1, the introduction of a cyano group onto the pyridyl ring is carried out 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. This novel method described in EP1650204A involves the introduction of a cyano group after the formation of the triazole ring.

International Publication No. 2014017516 presents another route for the preparation of topiroxostat of formula 1, in which case the introduction of the cyano group onto the pyridyl ring is carried out prior to the formation of the triazole ring. To.

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

CN103724329B describes another method for the preparation of topiroxostat, as shown in the following scheme.

The above method has major drawbacks. EP1471065, EP1650204, WO 2014017516 and Yamamoto use cyanide species to introduce a cyano group into the pyridyl moiety. These types of reagents hydrolyze to produce hydrogen cyanide, a highly toxic chemical, and must be treated with special care. On the other hand, CN1037432429B has a drawback that it consists of a large number of steps, uses an expensive starting material, and has a low yield. In addition, this method involves the use of cyanur chloride, a toxic reagent. Therefore, it is really difficult to develop a new "green" method that avoids the use of cyanide species, results in higher yields, and is less likely to conflict with environmental issues.

The present invention avoids the use of dangerous reagents or lengthy and redundant processes, via novel intermediates, totopiroxostat of formula 1 or any pharmaceutically acceptable salt or hydrate thereof. Disclose new methods for the preparation of solvates or polymorphs.

The present invention avoids the use of cyanide species such as NaCN, HCN, KCN, TSMCN, CuCN, Zn (CN) ₂ , for the cyanation reaction of the pyridyl ring, the topyroxostat of formula 1 or any of them. Disclose new methods for the preparation of pharmaceutically acceptable salts, hydrates, solvates or polymorphs. This novel method results in the preparation of topiroxostat using a novel method for the introduction of cyano groups onto the pyridyl ring using cheaper and safer reagents.

The present invention discloses a novel method for the preparation of topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein the method is:
a) A step of 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.
[In the above equation, R ₁ and R ₂ are independently selected from hydrogen or carbamoyl groups, except that R ₁ and R ₂ are not the same];
b) Step of converting the compound of formula 6 into the compound of formula 7
[In the above formula, R ₁ and R ₂ are as defined in the above step (a)];
c) The step of converting the compound of formula 7 into topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
[In the above equation, R ₁ and R ₂ are as defined in step (a)]
including.

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

Another embodiment of the present invention is the topiroxostat of formula 1 or any pharmaceutically acceptable thereof of the compound of formula 6 [where R ₁ and R ₂ are as defined above]. Direct conversion to salts, hydrates, solvates or polymorphs.

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

Another embodiment of the invention discloses the conversion of R ₁ or R _{2 to} a cyano group in any step of the method when neither R ₁ nor R ₂ is hydrogen.

The present invention discloses a novel method 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 short and efficient synthetic procedures, topiroxostat of formula 1, or any pharmaceutically acceptable salt thereof. Disclose new methods for the preparation of hydrates, solvates or polymorphs. This novel method for topiroxostat uses a different method for the cyanation reaction on the pyridyl ring, characterized by the use of groups that can be easily converted to cyano groups.

The present invention describes a novel method for the preparation of topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein the method is:
a) The compound of formula 3a [in the formula, R ₁ is a carbamoyl group] and the compound of formula 5b [in the formula, R ₂ is hydrogen] are reacted in the presence of a base, and the compound of formula 6b [formula] is reacted. Among them, R ₁ is a carbamoyl group and R ₂ is hydrogen].
Alternatively, a') the compound of formula 3b [R ₁ is hydrogen] and the compound of formula 5a [R ₂ is a carbamoyl group] are reacted in the presence of a base, and the compound of formula 6c [in the formula, R ₁ ] is reacted. Is hydrogen and R ₂ is a carbamoyl group]
b) The compound of formula 6b obtained in step a) [in the formula, R ₁ is a carbamoyl group and R ₂ is hydrogen], and the compound of formula 7 [in the formula, R ₁ is a carbamoyl group. R ₂ is hydrogen]
Alternatively, b') the compound of formula 6c obtained in step a') [R ₁ is hydrogen and R ₂ is a carbamoyl group], and the compound of formula 7 [R ₁ is hydrogen and R ₂ is carbamoyl]. The process of converting to];
c) The compound of formula 7 obtained in step (b) or (b') is converted into topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. Includes the step of conversion.

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 process of the method and as salts. Therefore, the compounds of formulas 6 and 7 can be isolated as salts when the acid is used in steps a or b.
The present invention provides a method for preparing a novel intermediate of formula 6 from compounds of formulas 3 and 5, as described above.

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

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

Another embodiment of the present invention is a topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or solvate thereof of the compound of formula 6b or 6c prepared as described above. 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 a carbamoyl group can be performed in any step of the method described above.

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

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

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

All improvements to the above methods over prior art methods are the introduction of carbamoyl groups onto pyridyl groups and their conversion to cyano groups by the use of 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 in which steps a and b, or steps a'and b', can preferably be performed without isolation of intermediates.

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

The carbamoylation reaction is derived from TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl), NHPI (N-hydroxyphthalimide) or similar reagents, TEMPO [(2,2). , 6,6-tetramethylpiperidin-1-yl) oxyl], PINO (phthalimide-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 imino ether in the presence of an alcohol under basic or acidic conditions. The alcohol can be, for example, methanol, ethanol or a similar lower alkyl alcohol and is readily 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 to prepare imino ethers under acidic conditions. The imino ether then reacts with the compound of formula 5a or 5b to form the compound of formula 6b or 6c.

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

In any of the above embodiments, the cyclization reaction results in the formation of a triazole ring and is carried out in a temperature range from room temperature to the boiling point of the solvent used. Reflux conditions are preferred because they 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 above atmospheric pressure. Suitable equipment readily available on a small or industrial scale can be used to achieve pressures above 1 atmosphere. The pressure can be increased by closing the vessel airtightly, or can be increased artificially by using some inert gas such as argon. Increasing the pressure accelerates the reaction.

Alternatively, the cyclization reaction can be carried out by the addition of an acid. Preferred acids are inorganic acids, but strong organic acids are equally effective. Preferred inorganic acids are hydrohalic acid, sulfuric acid, hydrogen sulfide acid, nitric acid, phosphoric acid, boric acid and hydrochanic acid. Preferred organic acids are formic acid, oxalic acid, acetic acid, trifluoroacetic acid and benzoic acid.

Another sensitive feature of this reaction is reaction time. The reaction time is entirely dependent on the reaction temperature and pressure and falls within a range that avoids the formation of unwanted degradation products.

In all of the above embodiments, the conversion of carbamoyl groups to cyanide groups is readily retained in the presence of suitable dehydrating reagents in the appropriate solvent. Suitable dehydration reagents that can be used in the dehydration step are thionyl chloride (SOCl ₂ ), phosgen (COCl ₂ ), phosphorus pentachloride (PCl ₅ ), phosphoryl chloride (POCl ₃ ), trifluoromethanosulfonic acid anhydride [( CF ₃ SO ₂ ) ₂ O], trifluoroacetic anhydride [(CF ₃ CO) ₂ O], thionyl chloride, ethyldichlorophosphate (EtOPOCl ₂ ), phosphorus pentaoxide (P ₄ O ₁₀ ), phosphorus trioxide (P ₄₎ It is phosphorus oxide, such as O ₆ ) or a similar oxide, 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. The 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 hydroxides, sodium carbonate, potassium carbonate or similar carbonates, sodium hydrogen carbonate or similar hydrogen carbonates.

The solvent in the above step is a halogenating solvent such as dichloromethane, chloroform and a similar halogenating solvent, an amide solvent such as N, N'-dimethylformamide, dimethylacetamide or a similar amide solvent, diethyl ether, tetrahydrofuran, tert-butylmethyl. Ethers such as ethers 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. 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 reaction product contains a base, the product of the above reaction may be optionally isolated as a salt. This salt can be formed from the acid produced by the dehydrating agent. For example, trifluoroacetic anhydride forms a trifluoroacetic acid salt of the compound of formula 1. Alternatively, other acids may be additionally used in this step of the method for the preparation of salts of the compounds of formula 1. The salt thus formed does not necessarily have to be a pharmaceutically acceptable salt.

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

In a preferred embodiment, steps a and b, or steps a'and b', are performed without isolation of 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 retained under these conditions, which is the triazole ring. Brings the formation of.

In another embodiment described above, conversion of a compound of formula 6b or 6c to a compound of formula 1 can be carried out simultaneously with appropriate selection of reagents.
Reagents capable of acting as a dehydrating agent and producing 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 polymorphs of the compounds of formula 1 were characterized according to the patent application of WO 2014017515.

Example 1
Preparation of 2-Carbamoyl-4-cyano-Pyridine (3a) 3 L 4-port r.S. with magnetic stirrer, thermometer and 500 mL addition funnel. b. The flask is filled 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. M. A solution of formamide (200 ml) in water is filled in an 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.I. M. Add water. The solvent is distilled off under reduced pressure. Filter the warm suspension. Wet cake with 500 mL of D. 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 (500MHz, 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) In a 2 L hydrogenator equipped with a magnetic bar, 115 g of 2- Carbamoyl-4-cyano-pyridine (3a) is subsequently charged with 1150 mL of methanol. 26.6 g of sodium methoxide is added in small portions at room temperature. The suspension is placed under stirring for 2 hours to form the corresponding imino ether. After consumption of the starting material, 106.9 g of isoniazid hydrazide (5b) is added. The resulting suspension is heated to 90 ° C. for 2 hours under pressure (4 bar). The reaction is heated to 100 ° C. for 6-10 hours under stirring and pressure (4 bar). The suspension was filtered off, the wet cake was washed with 200 ml of methanol, dried under reduced pressure and 121 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-. 3-Il) Obtain picoline amide 7.
The bar filtrate is evaporated and dried to give 185 g of crude product. The crude product is dissolved in 555 ml of DM water. The resulting suspension is heated at 80 ° C. for 2 hours and cooled at room temperature. Filter the suspension. The wet cake was washed with 200 ml of methanol, dried under reduced pressure and added 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 (500MHz, 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-mouth r. equipped with bar magnetic bar and thermometer. b. The flask is filled with 10.0 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) picoline amide (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 placed 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. Cool the suspension to room temperature and filter. The wet cake was washed with 200 ml of chilled methanol, dried under reduced pressure and 7.6 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl). Obtain a 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 was added to D.I. 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 small portions at room temperature (pH = 10). 12.9 ml of HCl (6N) (pH = 7) is added dropwise at room temperature. The reaction mixture is placed under stirring for 5 hours. The reaction is monitored by TLC and upon completion, the pale yellow solid is filtered off, washed with 2x50 ml cold water and dried under reduced pressure at 80 ° C. to give 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, 117.2.

Example 4
Preparation of topiroxostat 250 ml three-mouth r. Equipped with magnetic bar and thermometer. b. The flask is filled with 10.0 g of 4- (5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl) picoline amide (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 placed under stirring at room temperature for 1 hour. The reaction is monitored by TLC and after completion, the solvent is evaporated to form a crude API. The crude solid is dissolved in 50 ml of DCM and heated at 40 ° C. for 1 hour. Cool the suspension to room temperature and filter. The wet cake is washed with 10 ml DCM and dried under reduced pressure to give 6.5 g of 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, 117.2.

Example 5
Preparation of topiroxostat 250 ml three-mouth r. Equipped with magnetic bar, water condenser and thermometer. b. The flask is filled 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). The crude solid is dissolved in 50 ml of toluene and evaporated to remove excess POCl ₃ to give 10 g of a crude mixture (API HCl salt).

1H-NMR (500MHz, 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 a saturated Na ₂ CO ₃ solution over 1 hour with stirring to maintain the pH above 7. The resulting suspension is filtered off, washed with 2x50 ml cold water and dried under reduced pressure at 80 ° C. to give 7.1 g topiroxostat as crystal type 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 with 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 by D.I. M. Wash with water (2x10 ml) and dry under reduced pressure at 80 ° C. overnight to give 2.48 g of topiroxostat as crystal type II.

Claims (15)

A method for the preparation of topiroxostat of formula 1, or any pharmaceutically acceptable salt, hydrate, solvate and polymorph thereof:
a) A step of 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.
[In the above equation, R ₁ and R ₂ are independently selected from hydrogen or carbamoyl groups, except that R ₁ and R ₂ are not the same];
b) Step of converting the compound of formula 6 into the compound of formula 7
[In the above equation, R ₁ and R ₂ are as defined above];
c) The step of converting the compound of formula 7 into the topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate and polymorph thereof.
[In the above equation, R ₁ and R ₂ are as defined above]
How to include. Compound of formula 6
R ₁ and R ₂ are independently selected from hydrogen or carbamoyl groups, except that R ₁ and R ₂ are not the same and are compounds of formula 3.
And the compound of formula 5
R ₁ and R ₂ are defined as described above, comprising reacting with. Compound of formula 7
R ₁ and R ₂ are as defined in claim ₁ and are compounds of formula 6.
Compound of formula 7
R ₁ and R ₂ include the conversion to, as defined in claim 1. The compound of formula 3 in the presence of a base
And the compound of formula 5
To react with the compound of formula 6
30. The method of claim 3, further comprising forming any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof thereof. The method of claim 1, wherein steps a and b are performed without isolating the compound of formula 6. Equation 1
A method for the preparation of topiroxostat or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof:
a) A step of 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.
[In the above equation, R ₁ and R ₂ are defined as in claim 1];
b) The step of converting the compound of formula 6 into the topiroxostat of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
[In the above equation, R ₁ and R ₂ are defined as above]
How to include. Compound of formula 7 in the presence of dehydrating agent
A method for the preparation of topiroxostat, which comprises the conversion of topiroxostat to topiroxostat. A claim that the compound of formula 1 is isolated as a salt from the reaction of step c and then converted to a free base, pharmaceutically acceptable salt, hydrate, solvate or polymorph of the compound of formula 1. Item 1. The method according to Item 1 . R ₁ is a carbamoyl group, R ₂ is hydrogen, and the compound of formula 3 is the compound of formula 3a.
Here, R ₁ is a carbamoyl group, and the compound of formula 5 is the compound of formula 5b.
Where R ₂ is hydrogen and the compound of formula 6 is the compound of formula 6b.
The method according to any one of claims 1 to 8. R ₁ is hydrogen, R ₂ is a carbamoyl group, and the compound of formula 3 is the compound of formula 3b.
Where R ₁ is hydrogen and the compound of formula 5 is the compound of formula 5a.
Where R ₂ is a carbamoyl group and the compound of formula 6 is of formula 6c.
The method according to any one of claims 1 to 8, which is a compound of the above. Compound of formula 1
And purification of the compound of formula 1 comprising conversion of said salt to a compound of formula 1 or any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. Method for. Topiroxostat of formula 1
Or any compound of formula 6b for the formation of any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
Where R ₁ is a carbamoyl group and R ₂ is hydrogen, use. Topiroxostat of formula 1
Or any compound of formula 6c for the production of any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
Where R ₁ is hydrogen and R ₂ is a carbamoyl group, use. Topiroxostat of formula 1 where R ₁ and R ₂ are independently selected from hydrogen or carbamoyl groups, except that R ₁ and R ₂ are not the same.
Or any compound of formula 7 for the production of any pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
Use of. A compound of formula 7 in which R ₁ and R ₂ are defined as in claim 1.
..