CN113666909A - Preparation method of topiroxostat - Google Patents

Preparation method of topiroxostat Download PDF

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CN113666909A
CN113666909A CN202010404610.3A CN202010404610A CN113666909A CN 113666909 A CN113666909 A CN 113666909A CN 202010404610 A CN202010404610 A CN 202010404610A CN 113666909 A CN113666909 A CN 113666909A
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reaction
catalyst
acid
room temperature
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徐杰
翟立海
梁茂征
谢印杰
刘忠
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Lunan Pharmaceutical Group Corp
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof

Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of topiroxostat. The preparation method comprises the steps of reacting 2-cyanopyridine with formamide to obtain 2-cyano-4-carbamoyl-pyridine, continuously reacting the 2-cyano-4-carbamoyl-pyridine with isoniazid to obtain a key intermediate 4-pyridine formylhydrazine-N '- (2-cyanopyridine-4-carbonylimino) and closing a ring by 4-pyridine formylhydrazine-N' - (2-cyanopyridine-4-carbonylimino) to obtain the topirostat. The invention provides a novel method for synthesizing topiroxostat, which avoids using highly toxic chemical reagents, replaces the traditional catalyst with a green catalyst, has milder reaction, is economic and environment-friendly, has higher yield and is suitable for industrial production.

Description

Preparation method of topiroxostat
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of topiroxostat.
Background
Topiroxostat (Topiroxostat), a new-generation high-selectivity reversible xanthine oxidase inhibitor co-developed by fuji co-ltd and san and chemistry in japan, was approved in japan for marketing in 2013 in 6 months, and has two advantages over the currently clinically applied anti-gout drugs: most of the compounds only have inhibitory effect on reduced xanthine oxidase, and topiroxostat has obvious inhibitory effect on both oxidized and reduced xanthine oxidase, so that the effect of reducing uric acid is stronger and more durable; other purine analogs inevitably cause other enzymatic activities involved in purine and pyridine metabolism. The product has the advantages of strong effect of reducing uric acid, less adverse reaction, good safety, etc. The chemical name of the compound is 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2, 4-triazole, and the structural formula is as follows:
Figure BDA0002490827360000011
at present, the synthesis process of topiroxostat mainly comprises the steps of obtaining isonicotinyl compounds through multi-step reactions, then cyclizing with 4-cyanopyridine to obtain topiroxostat, for example, the original Chinese patent application CN1561340 and the European patent EP1471065 both disclose that methyl isonicotinate-N-oxide is prepared into 2-cyano isonicotinate methyl ester through Reiser Henze reaction, then the 2-cyano isonicotinate methyl ester is prepared into hydrazide, and finally the toliroxostat is prepared through a method of condensing the isonicotinate methyl ester with 4-cyanopyridine, wherein the specific preparation process is as follows:
Figure BDA0002490827360000012
the synthetic method has the defects that a cyano group is introduced through a Reissert Henze reaction, but the reaction product trimethylsilylcyanide used in the reaction is a highly toxic compound, and has the disadvantages of high price, high operation risk and great environmental pollution.
In order to further solve the problem of using trimethyl silylcyanide, chinese patent application CN104151297 discloses that methyl isonicotinate-N-oxide is used as the starting material, in the presence of copper catalyst (CuX), metal cyanide and dimethylcarbamoyl chloride, to generate 2-cyanoisonicotinate methyl ester, hydrazinolysis is performed to obtain 2-cyanoisonicotinazine, and finally condensation is performed with 4-cyanopyridine to obtain crude tolpiroxostat, the synthetic route is as follows:
Figure BDA0002490827360000021
in this process, cyanide is used: sodium cyanide, potassium cyanide, zinc cyanide and copper cyanide are also highly toxic reaction reagents, and have high operational risk and great environmental pollution.
In order to avoid the application of the trimethyl silicon cyanide virulent compound and the virulent metal cyanide, the Chinese patent application CN103724329A reports that methyl isonicotinate is used as a raw material, and after amidation, the methyl isonicotinate is dehydrated to form a cyano group, so that the virulent cyanide is avoided, and the specific reaction route is as follows:
Figure BDA0002490827360000022
but the amidation reaction process is complicated, the requirement on production equipment is high, the yield is low, and the production cost is increased.
Chinese patent application CN108101840 uses 4-cyanopyridine as raw material to react with hydrazine hydrate to obtain 4-pyridine azomethine acid hydrazine, and then carries out amidation reaction to obtain a compound IV; under the action of a catalyst, carrying out ring closure on the compound IV to obtain topiroxostat, wherein the reaction route is as follows:
Figure BDA0002490827360000023
although the reaction route is short, the amidation reaction of compound III and compound IIB requires a condensation reagent, which increases the reaction cost, and the reaction yield and purity are not high (comparative example).
Therefore, the problem that the existing Topiroxostat preparation process uses a virulent cyanidation reagent, the reaction condition is harsh, the process route is long, the raw material cost is high, the yield is low and the like is still solved by exploring a process route more suitable for industrial production.
Disclosure of Invention
In order to solve the problems of severe toxic cyaniding reagent, harsh reaction conditions, longer process route, higher raw material cost, lower yield and the like in the preparation process of topiroxostat in the prior art, the invention provides a novel preparation method of topiroxostat.
The invention is realized by the following technical scheme:
a preparation method of topiroxostat comprises the following steps: step 1, reacting a compound II with formamide under the action of a catalyst to obtain a compound IV; step 2, dehydrating and condensing the compound IV and the compound V to obtain a compound VI; and 3, carrying out a ring-closing reaction on the compound VI in the step 3 to obtain topiroxostat I, wherein the synthetic route is as follows:
Figure BDA0002490827360000031
preferably, the above steps are described in further detail in the following sections:
step 1 preparation of Compound IV
Preparation of compound IV: and adding the compound II, the catalyst and the compound III, namely formamide, into an organic solvent, stirring and dissolving at a controlled temperature, adding a free radical initiator, and performing crystallization after TLC monitoring reaction to obtain a target product compound IV.
Preferably, the catalyst can be selected from one or a combination of inorganic acid such as sulfuric acid, hydrochloric acid and nitric acid; or organic acids such as formic acid, acetic acid, or combinations thereof, with sulfuric acid being particularly preferred.
Preferably, the radical initiator is one or a combination of ammonium persulfate, ceric ammonium nitrate, sodium persulfate and potassium persulfate, wherein ammonium persulfate is particularly preferred.
In a preferable embodiment, the feeding molar ratio of the compound II, the compound III, the catalyst and the radical initiator is 1: 4.0-6.0: 0.2-0.6: 1.2-2.0, and particularly preferably 1:5.0:0.4: 1.5.
Preferably, the organic solvent is one of toluene, 1, 4-dioxane, 1, 2-dichloroethane or a combination thereof, wherein toluene is particularly preferred.
In a preferred scheme, the reaction temperature is 60-80 ℃, and particularly preferably 70-75 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after the reaction is finished, adding purified water into the reaction solution, cooling to room temperature for crystallization, filtering, washing a filter cake with purified water, then washing with ethanol, and drying in vacuum to obtain an intermediate compound IV.
Step 2 preparation of compound VI:
adding the compound IV, the compound V and a catalyst into an organic solvent, controlling the temperature, adding a dehydrating agent, heating and stirring for reaction after the addition is finished, and crystallizing to obtain a compound VI after the TLC monitoring reaction is finished.
Preferably, the catalyst comprises Lewis acid or Lewis base, and the Lewis acid is selected from one or the combination of aluminum trichloride, titanium tetrachloride, boron trifluoride and ferric tribromide; the Lewis base is selected from one or the combination of triethylamine, potassium carbonate and sodium bicarbonate, wherein triethylamine is particularly preferred.
Preferably, the dehydrating agent is one or a combination of trifluoroacetic anhydride, phosphorus oxychloride and thionyl chloride, and trifluoroacetic anhydride is particularly preferred.
Preferably, the organic solvent is one or a combination of acetonitrile, methanol, ethanol, n-butanol, dioxane and 1, 2-dichloroethane, and particularly preferably acetonitrile.
In a preferred scheme, the feeding molar ratio of the compound IV, the compound V, the catalyst and the dehydrating agent is as follows: 1: 1.0-2.0: 1.1-2.0: 1.0-1.5, especially preferably 1:1.2:1.5: 1.2.
In a preferred scheme, the temperature of the dehydrating agent is 0-20 ℃.
In a preferred scheme, the reaction temperature is 50-70 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: and cooling the reaction liquid to room temperature, adding purified water, adjusting the pH value of the system to 6.0-7.0, crystallizing at room temperature, filtering, and drying in vacuum to obtain an intermediate compound VI.
Step 3 preparation of topiroxostat
And adding the compound VI into an organic solvent, adding a catalyst, and stirring and reacting under the protection of inert gas at a controlled temperature to obtain the topiroxostat I.
Preferably, the catalyst is a base or an organic acid, and the base can be selected from one or a combination of sodium carbonate, sodium bicarbonate, sodium methoxide and sodium ethoxide; the organic acid can be selected from one or the combination of p-toluenesulfonic acid, formic acid and acetic acid, wherein sodium carbonate is particularly preferred.
In a preferred embodiment, the feeding molar ratio of the compound VI to the catalyst is 1: 1.1-2.0, and 1:1.2 is particularly preferred.
Preferably, the organic solvent is one or a combination of acetonitrile, ethanol, dioxane, 1, 2-dichloroethane and N, N-dimethylformamide, wherein acetonitrile is preferred.
In a preferred scheme, the reaction temperature is 60-90 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: and after the reaction is finished, cooling the reaction liquid to room temperature, adjusting the pH value of the reaction liquid to 6.0-7.0, crystallizing at room temperature, filtering, leaching a filter cake with purified water, and drying in vacuum to obtain the topiroxostat.
Compared with the prior art, the invention has the following technical effects:
1. the novel method for preparing the topiroxostat simply, conveniently and efficiently is provided, the whole synthesis method is simple and convenient to operate, the reaction yield is high, and the purity of the obtained product is high;
2. the method uses 2-cyano-4-carbamoyl-pyridine to react with isoniazid to prepare the topiroxostat key intermediate 4-pyridine formylhydrazine-N' - (2-cyanopyridine-4-carbonylimino) instead of the traditional complex condensation reaction of cyano.
In conclusion, the invention provides a new method for topiroxostat, which avoids using highly toxic chemical reagents, replaces the traditional catalyst with a green catalyst, has milder reaction, is economic and environment-friendly, has higher yield, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative, not limiting, and therefore, the present invention is susceptible to modification in the form of the method of the present invention.
Preparation of Compound IV
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL of toluene into a 5L three-necked flask at room temperature, stirring and dissolving, then dropwise adding concentrated sulfuric acid (39.23g, 0.4mol), heating to 70-75 ℃ after dropwise adding, quickly adding formamide aqueous solution (225.20g, 5.0mol), adding ammonium persulfate (342.30g, 1.5mol) saturated aqueous solution at the beginning of dropwise adding, keeping the temperature for reaction at 70-75 ℃, adding 1000mL of purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature for crystallization for 2 hours, filtering, washing a filter cake to neutrality with purified water, washing with 200mL of ethanol, and vacuum drying for 12 hours to obtain the 2-cyano-4-carbamoyl-pyridine, wherein the yield is 98.7% and the purity is 99.88%.
Example 2
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL of toluene into a 5L three-necked bottle at room temperature, stirring and dissolving, then dropwise adding concentrated sulfuric acid (39.23g, 0.4mol), after dropwise adding, heating to 70-75 ℃, quickly adding formamide aqueous solution (180.16g, 4.0mol), after dropwise adding, beginning to add ammonium persulfate (342.30g, 1.5mol) saturated aqueous solution, after dropwise adding, carrying out heat preservation reaction at 70-75 ℃, adding 1000mL of purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature for crystallization for 2 hours, filtering, washing a filter cake to neutrality with purified water, washing with 200mL of ethanol, and carrying out vacuum drying for 12 hours to obtain the 2-cyano-4-carbamoyl-pyridine, wherein the yield is 94.2% and the purity is 99.79%.
Example 3
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL1, 2-dichloroethane into a 5L three-necked flask at room temperature, stirring for dissolving, then dropwise adding hydrochloric acid (14.60g, 0.4mol), after dropwise adding, heating to 70-75 ℃, rapidly adding formamide aqueous solution (270.24g, 6.0mol), after dropwise adding, adding ammonium persulfate (342.30g, 1.5mol) saturated aqueous solution, after dropwise adding, carrying out heat preservation reaction at 70-75 ℃, adding 1000mL purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature for crystallization for 2 hours, filtering, washing a filter cake to neutrality by purified water, then washing by 200mL ethanol, carrying out vacuum drying for 12 hours, preparing 2-cyano-4-carbamoyl-pyridine, wherein the yield is 93.6%, and the HPLC purity is 99.75%.
Example 4
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL1, 4-dioxane into a 5L three-neck flask at room temperature, stirring and dissolving, then dropwise adding formic acid (18.41g, 0.4mol), heating to 70-75 ℃, quickly adding formamide aqueous solution (157.64g, 3.5mol), after dropwise adding, adding ammonium persulfate (342.30g, 1.5mol) saturated aqueous solution, after dropwise adding, keeping the temperature at 70-75 ℃ for reaction, adding 1000mL purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature for crystallization for 2 hours, filtering, washing a filter cake to neutrality by purified water, washing by 200mL ethanol, vacuum drying for 12 hours, preparing 2-cyano-4-carbamoyl-pyridine, wherein the yield is 88.7%, and the purity is 99.71% by HPLC.
Example 5
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL of 1.2-dichloroethane into a 5L three-necked flask at room temperature, stirring for dissolving, then dropwise adding acetic acid (24.02g, 0.4mol), after dropwise adding, heating to 70-75 ℃, quickly adding formamide aqueous solution (292.76g, 6.5mol), after dropwise adding, beginning to add ammonium persulfate (342.30g, 1.5mol) saturated aqueous solution, after dropwise adding, carrying out heat preservation reaction at 70-75 ℃, adding 1000mL of purified water into a reaction solution monitored by TLC, cooling to room temperature for crystallization for 2 hours, filtering, washing a filter cake to be neutral by using purified water, washing by using 200mL of ethanol, carrying out vacuum drying for 12 hours, and preparing the 2-cyano-4-carbamoyl-pyridine, wherein the yield is 86.6%, and the purity of HPLC is 99.65%.
Example 6
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL of toluene into a 5L three-necked flask at room temperature, stirring and dissolving, then dropwise adding concentrated sulfuric acid (19.62g, 0.2mol), after dropwise adding, heating to 60-65 ℃, quickly adding formamide aqueous solution (225.20g, 5.0mol), after dropwise adding, beginning to add ceric ammonium nitrate (822.33g, 1.5mol) saturated aqueous solution, after dropwise adding, carrying out heat preservation reaction at 60-65 ℃, adding 1000mL of purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature for crystallization for 2 hours, filtering, washing a filter cake to neutrality with purified water, then washing with 200mL of ethanol, and carrying out vacuum drying for 12 hours to obtain the 2-cyano-4-carbamoyl-pyridine, wherein the yield is 94.3% and the purity is 99.82%.
Example 7
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL of toluene into a 5L three-necked flask at room temperature, stirring and dissolving, then dropwise adding concentrated sulfuric acid (58.85g, 0.6mol), after dropwise adding, heating to 75-80 ℃, quickly adding formamide aqueous solution (225.20g, 5.0mol), after dropwise adding, beginning to add sodium persulfate (170.45g, 1.2mol) saturated aqueous solution, after dropwise adding, carrying out heat preservation reaction at 75-80 ℃, adding 1000mL of purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature, crystallizing for 2 hours, filtering, washing a filter cake to neutrality with purified water, washing with 200mL of ethanol, and carrying out vacuum drying for 12 hours to obtain the 2-cyano-4-carbamoyl-pyridine, wherein the yield is 95.2% and the purity is 99.77%.
Example 8
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL of toluene into a 5L three-necked bottle at room temperature, stirring and dissolving, then dropwise adding concentrated sulfuric acid (9.81g, 0.1mol), after dropwise adding, heating to 80-85 ℃, quickly adding formamide water solution (225.20g, 5.0mol), after dropwise adding, beginning to add potassium persulfate (540.64g, 2.0mol) saturated water solution, after dropwise adding, carrying out heat preservation reaction at 80-85 ℃, adding 1000mL of purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature for crystallization for 2 hours, filtering, washing a filter cake to neutrality with purified water, then washing with 200mL of ethanol, and carrying out vacuum drying for 12 hours to obtain the 2-cyano-4-carbamoyl-pyridine, wherein the yield is 87.2% and the purity is 99.71%.
Example 9
Adding 2-cyanopyridine (104.11g, 1.0mol) and 1000mL of toluene into a 5L three-neck flask at room temperature, stirring and dissolving, then dropwise adding concentrated sulfuric acid (78.46g, 0.8mol), after dropwise adding, heating to 55-60 ℃, quickly adding formamide aqueous solution (225.20g, 5.0mol), after dropwise adding, beginning to add ammonium persulfate (502.04g, 2.2mol) saturated aqueous solution, after dropwise adding, carrying out heat preservation reaction at 55-60 ℃, adding 1000mL of purified water into a reaction solution after TLC monitoring reaction, cooling to room temperature, crystallizing for 2 hours, filtering, washing a filter cake to neutrality with purified water, washing with 200mL of ethanol, and carrying out vacuum drying for 12 hours to prepare the 2-cyano-4-carbamoyl-pyridine, wherein the yield is 85.5% and the purity is 99.67%.
Preparation of Compound VI
Example 10
Into a 5L three-necked flask, compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500mL of acetonitrile were added at room temperature, triethylamine (15.18g, 0.15mol) was added, and stirring was carried out for 1 hour; adding isoniazid (16.46g, 0.12mol), controlling the temperature to be 10 ℃, dropwise adding a dehydrating agent trifluoroacetic anhydride (25.20g, 0.12), heating to 60-65 ℃, stirring for reacting for 6 hours, monitoring by TLC to finish the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 98.5%, and the HPLC purity is 99.89%.
Example 11
Into a 5L three-necked flask, compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500mL of methanol were charged at room temperature, and boron trifluoride (10.17g, 0.15mol) was added and stirred for 1 hour; adding isoniazid (13.71g, 0.1mol), controlling the temperature to be 10 ℃, dropwise adding a dehydrating agent trifluoroacetic anhydride (25.20g, 0.12), after dropwise adding, heating to 50-55 ℃, stirring and reacting for 6 hours, monitoring by TLC to complete the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 95.6%, and the HPLC purity is 99.82%.
Example 12
Compound IV, 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol), and 500mL ethanol were added to a 5L three-necked flask at room temperature, iron tribromide (44.33g, 0.15mol) was added, and stirring was carried out for 1 hour; adding isoniazid (27.42g, 0.2mol), controlling the temperature to be 10 ℃, dropwise adding a dehydrating agent trifluoroacetic anhydride (25.20g, 0.12), heating to 55-60 ℃, stirring and reacting for 6 hours after dropwise adding, monitoring by TLC to finish the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 93.4% and the HPLC purity is 99.75%.
Example 13
To a 5L three-necked flask, compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500mL of n-butanol were added at room temperature, sodium bicarbonate (12.60g, 0.15mol) was added, and stirred for 1 hour; adding isoniazid (30.17g, 0.22mol), controlling the temperature to be 10 ℃, dropwise adding a dehydrating agent trifluoroacetic anhydride (25.20g, 0.12), after dropwise adding, heating to 70-75 ℃, stirring and reacting for 6 hours, monitoring by TLC to complete the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 88.4%, and the HPLC purity is 99.70%.
Example 14
Into a 5L three-necked flask, compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500mL dioxane were added at room temperature, triethylamine (11.13g, 0.11mol) was added, and stirring was carried out for 1 hour; adding isoniazid (16.46g, 0.12mol), controlling the temperature to be 10 ℃, dropwise adding a dehydrating agent phosphorus oxychloride (18.40g, 0.12), heating to 70-75 ℃ after dropwise adding, stirring and reacting for 6 hours, monitoring by TLC to finish the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 94.2%, and the HPLC purity is 99.82%.
Example 15
Compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500ml of 1.2-dichloroethane, were added to a 5L three-necked flask at room temperature, triethylamine (20.24g, 0.2mol) was added, and the mixture was stirred for 1 hour; adding isoniazid (16.46g, 0.12mol), controlling the temperature to be 10 ℃, dropwise adding a dehydrating agent thionyl chloride (14.28g, 0.12), heating to 60-65 ℃ after dropwise adding, stirring for reacting for 6 hours, monitoring by TLC to finish the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 95.5% and the HPLC purity is 99.83%.
Example 16
Compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500ml of 1.2-dichloroethane, were added to a 5L three-necked flask at room temperature, triethylamine (10.12g, 0.1mol) was added, and the mixture was stirred for 1 hour; adding isoniazid (16.46g, 0.12mol), controlling the temperature to be 10 ℃, dropwise adding a dehydrating agent trifluoroacetic anhydride (25.20g, 0.12), heating to 60-65 ℃, stirring and reacting for 6 hours, monitoring by TLC to complete the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 92.2% and the HPLC purity is 99.78%.
Example 17
Compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500ml of 1.2-dichloroethane, were added to a 5L three-necked flask at room temperature, triethylamine (22.26g, 0.22mol) was added, and the mixture was stirred for 1 hour; adding isoniazid (16.46g, 0.12mol), dropwise adding a dehydrating agent trifluoroacetic anhydride (25.20g, 0.12) at the temperature of 0 ℃, heating to 60-65 ℃ after dropwise adding, stirring for reacting for 6 hours, monitoring by TLC to complete the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 87.6% and the HPLC purity is 99.68%.
Example 18
Into a 5L three-necked flask, compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500mL of acetonitrile were added at room temperature, and aluminum trichloride (20.0g, 0.15mol) was added and stirred for 1 hour; adding isoniazid (16.46g, 0.12mol), dropwise adding a dehydrating agent trifluoroacetic anhydride (21.0g, 0.1mol) at the temperature of 0 ℃, heating to 60-65 ℃ after dropwise adding, stirring for reacting for 6 hours, monitoring by TLC to finish the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 94.3%, and the HPLC purity is 99.82%.
Example 19
Into a 5L three-necked flask, compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500mL of acetonitrile were added at room temperature, titanium tetrachloride (28.45g, 0.15mol) was added, and stirring was carried out for 1 hour; adding isoniazid (16.46g, 0.12mol), controlling the temperature to be 20 ℃, dropwise adding a dehydrating agent trifluoroacetic anhydride (31.50g, 0.15mol), heating to 60-65 ℃, stirring for reacting for 6 hours, monitoring by TLC to complete the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 92.3%, and the HPLC purity is 99.78%.
Example 20
To a 5L three-necked flask, compound IV, i.e., 2-cyano-4-carbamoyl-pyridine (26.60g, 0.1mol) and 500mL of acetonitrile were added at room temperature, potassium carbonate (20.73g, 0.15mol) was added, and stirred for 1 hour; adding isoniazid (16.46g, 0.12mol), controlling the temperature to be 20 ℃, dropwise adding a dehydrating agent trifluoroacetic anhydride (35.71g, 0.17mol), after dropwise adding, heating to 60-65 ℃, stirring and reacting for 6 hours, monitoring by TLC to complete the reaction, cooling the reaction solution to room temperature, adding 500mL of purified water, adjusting the pH of the system to 6.0-7.0, crystallizing at normal temperature, filtering, and drying in vacuum to obtain a compound VI, wherein the yield is 87.3%, and the HPLC purity is 99.67%.
Topiroxostat preparation
Example 21
Adding a compound VI (26.61g, 0.1mol) and 500mL of acetonitrile into a reaction bottle at room temperature, adding sodium carbonate (12.72g, 0.12mol), controlling the temperature to be 75-80 ℃ under the protection of nitrogen gas to carry out a ring-closing reaction, stirring for 12 hours, monitoring by TLC, cooling the reaction liquid to the room temperature if the reaction is not finished, adjusting the pH of the reaction liquid to be 6.0-7.0, stirring at the room temperature to crystallize, filtering, leaching a filter cake by purified water and ethanol respectively, and drying at the temperature of 60 ℃ in vacuum to obtain Topiroxostat, wherein the yield is 98.6%, and the HPLC purity is 99.96%.
Example 22
Adding a compound VI (26.61g, 0.1mol) and 500mL of acetonitrile into a reaction bottle at room temperature, adding sodium carbonate (11.66g, 0.11mol), controlling the temperature to be 60-65 ℃ under the protection of nitrogen gas to carry out a ring-closing reaction, stirring for 12 hours, carrying out TLC monitoring, cooling the reaction liquid to the room temperature if the reaction is not finished, adjusting the pH of the reaction liquid to be 6.0-7.0, stirring at the room temperature to crystallize, filtering, leaching a filter cake with purified water and ethanol respectively, and drying at the temperature of 60 ℃ in vacuum to obtain Topiroxostat, wherein the yield is 96.6% and the HPLC purity is 99.88%.
Example 23
Adding a compound VI (26.61g, 0.1mol) and 500mL of dioxane into a reaction bottle at room temperature, adding sodium carbonate (21.20g, 0.2mol), controlling the temperature to be 85-90 ℃ under the protection of nitrogen gas to carry out ring-closing reaction, stirring for 12 hours, monitoring by TLC, cooling the reaction liquid to the room temperature if the reaction is not finished, adjusting the pH of the reaction liquid to be 6.0-7.0, stirring at the room temperature for crystallization, filtering, leaching filter cakes by purified water and ethanol respectively, and drying in vacuum at 60 ℃ to obtain Topiroxostat, wherein the yield is 94.5% and the HPLC purity is 99.79%.
Example 24
Adding a compound VI (26.61g, 0.1mol) and 500mL of acetonitrile into a reaction bottle at room temperature, adding sodium carbonate (10.60g, 0.1mol), controlling the temperature to be 55-60 ℃ under the protection of nitrogen gas to carry out a ring-closing reaction, stirring for 12 hours, monitoring by TLC, cooling the reaction liquid to the room temperature if the reaction is not finished, adjusting the pH of the reaction liquid to be 6.0-7.0, stirring at the room temperature to crystallize, filtering, leaching a filter cake by purified water and ethanol respectively, and drying at the temperature of 60 ℃ in vacuum to obtain Topiroxostat, wherein the yield is 89.6% and the HPLC purity is 99.70%.
Example 25
Adding a compound VI (26.61g, 0.1mol) and 500mL of acetonitrile into a reaction bottle at room temperature, adding sodium carbonate (23.32g, 0.1mol), controlling the temperature to be 75-80 ℃ under the protection of nitrogen gas to carry out a ring-closing reaction, stirring for 12 hours, monitoring by TLC, cooling the reaction liquid to the room temperature if the reaction is not finished, adjusting the pH of the reaction liquid to be 6.0-7.0, stirring at the room temperature to crystallize, filtering, leaching a filter cake by purified water and ethanol respectively, and drying at the temperature of 60 ℃ in vacuum to obtain Topiroxostat, wherein the yield is 87.9% and the HPLC purity is 99.67%.
Example 26
Adding a compound VI (26.61g, 0.1mol) and 500mL of N, N-dimethylformamide into a reaction bottle at room temperature, adding sodium methoxide (6.48g, 0.12mol), controlling the temperature to be 90-95 ℃ under the protection of nitrogen gas to carry out ring-closure reaction, stirring and reacting for 12 hours, monitoring by TLC, cooling the reaction liquid to the room temperature if the reaction is not finished, adjusting the pH of the reaction liquid to be 6.0-7.0, stirring and crystallizing at the room temperature, filtering, leaching filter cakes by purified water and ethanol respectively, and drying in vacuum at 60 ℃ to obtain Topiroxostat, wherein the yield is 96.2%, and the HPLC purity is 99.81%.
Example 27
Adding a compound VI (26.61g, 0.1mol) and 500mL of 1, 2-dichloroethane into a reaction bottle at room temperature, adding p-toluenesulfonic acid (20.66g, 0.12mol), controlling the temperature to be 75-80 ℃ under the protection of nitrogen gas to perform a ring-closing reaction, stirring and reacting for 12 hours, monitoring by TLC, cooling the reaction solution to the normal temperature after the reaction is not completed, adjusting the pH of the reaction solution to 6.0-7.0, stirring and crystallizing at the normal temperature, filtering, leaching filter cakes by purified water and ethanol respectively, and performing vacuum drying at 60 ℃ to obtain topirostat, wherein the yield is 95.6%, and the HPLC purity is 99.78%.
Example 28
Adding a compound VI (26.61g, 0.1mol) and 500mL of ethanol into a reaction bottle at room temperature, adding acetic acid (7.21g, 0.12mol), controlling the temperature to be 55-60 ℃ under the protection of nitrogen gas to carry out a ring-closing reaction, stirring for 12 hours, monitoring by TLC, cooling the reaction liquid to the room temperature if the reaction is not finished, adjusting the pH of the reaction liquid to be 6.0-7.0, stirring at the room temperature to crystallize, filtering, leaching a filter cake by purified water and ethanol respectively, and drying at the temperature of 60 ℃ in vacuum to obtain Topiroxostat, wherein the yield is 94.2% and the HPLC purity is 99.75%.
Comparative examples
Adding 2.08kg of 4-cyanopyridine into a 20L reaction kettle, adding 10L of ethanol and 8.8g of sodium methoxide, heating to 40 ℃, stirring for 9h, and detecting by TLC that the raw materials are basically reacted completely; adding 5L of ethanol, 1.41kg of 85% hydrazine hydrate and 12ml of concentrated hydrochloric acid into another 20L reaction kettle, slowly pouring the reaction solution in the previous step, stirring at room temperature for 1h, and detecting by TLC that the raw materials completely react; removing most of the solvent by rotary evaporation at 35 ℃ to obtain a semi-oily solid, adding 15L of methyl tert-butyl ether, stirring at room temperature, filtering, and vacuum drying at 30 ℃ to obtain 2.31kg of pale yellow intermediate 4-pyridine methyl imino acid hydrazine, wherein the yield is 78.8 percent and the HPLC purity is 97.60 percent.
847g of compound 4-pyridine formiminium acid hydrazine is added into a 20L reaction kettle, 4.5L of DMF is added, 1.64Kg of EDC & HCl and 1.14Kg of HOBT are added, after stirring and clearing at room temperature, 934g of intermediate III are added, stirring is carried out at room temperature for 12h, and TLC detects that the raw materials are completely reacted; 4.5L of an aqueous solution of sodium hydrogencarbonate (719 g) and 9L of ethyl acetate were added and stirred at room temperature for 12 hours to precipitate a large amount of yellow solid, which was then filtered and air-dried at 50 ℃ to obtain 1.38kg of pale yellow solid, 4-pyridinecarbohydrazide-N' - (2-cyanopyridine-4-carboximidoyl), yield 84.8% and HPLC purity 98.70%.
1.20kg of intermediate 4-pyridinecarbohydrazide-N' - (2-cyanopyridine-4-carbonylimino) was placed in a 1L single-neck flask, 14L of ethanol and 280mL of acetic acid were added, and the mixture was stirred at a reflux temperature for 12 hours. And cooling the reaction solution to room temperature, filtering, leaching with a small amount of ethanol, and vacuum-drying the obtained solid at 80 ℃ to obtain 1.01Kg of topiroxostat with the yield of 83.2% and the HPLC purity of 98.80%.

Claims (10)

1. The preparation method of topiroxostat is characterized in that a compound II reacts with formamide under the action of a catalyst to obtain a compound IV; dehydrating and condensing the compound IV and the compound V to obtain a compound VI; the compound VI is subjected to a ring-closing reaction to obtain topiroxostat I, and the synthetic route is as follows:
Figure FDA0002490827350000011
2. the method of claim 1, comprising the steps of:
(1) preparation of compound IV: adding a compound II, a catalyst and a compound III, namely formamide, into an organic solvent, stirring and dissolving at a controlled temperature, adding a free radical initiator, and after the reaction is finished, crystallizing to obtain a target product compound IV;
(2) adding a compound IV, a compound V and a catalyst into an organic solvent, controlling the temperature, adding a dehydrating agent, heating, stirring, reacting, and crystallizing to obtain a compound VI after the reaction is finished;
(3) and adding the compound VI into an organic solvent, adding a catalyst, and reacting under the protection of inert gas at a controlled temperature to obtain the topiroxostat I.
3. The method according to claim 2, wherein the catalyst in step (1) can be selected from inorganic acids, such as one or a combination of hydrochloric acid, nitric acid, sulfuric acid; or an organic acid such as one of formic acid, acetic acid, or a combination thereof.
4. The method according to claim 2, wherein the radical initiator in step (1) is one of ammonium persulfate, ammonium ceric nitrate, sodium persulfate, potassium persulfate or a combination thereof.
5. The preparation method according to claim 2, wherein the compound II, the compound III, the catalyst and the radical initiator in the step (1) are fed in a molar ratio of 1: 4.0-6.0: 0.2-0.6: 1.2-2.0.
6. The preparation method according to claim 2, wherein the catalyst in step (2) can be Lewis acid or Lewis base, and the Lewis acid can be one of aluminum trichloride, titanium tetrachloride, boron trifluoride and ferric tribromide or a combination thereof; the lewis base may be one of triethylamine, potassium carbonate, sodium bicarbonate, or a combination thereof.
7. The preparation method according to claim 2, wherein the dehydrating agent in step (2) is one selected from trifluoroacetic anhydride, phosphorus oxychloride, thionyl chloride or a combination thereof.
8. The method according to claim 2, wherein the compound IV, the compound V, the catalyst and the dehydrating agent are fed in the step (2) in a molar ratio of: 1: 1.0-2.0: 1.1-2.0: 1.0-1.5.
9. The preparation method according to claim 2, wherein the catalyst in step (3) is a base or an organic acid, and the base can be selected from one or a combination of sodium carbonate, sodium bicarbonate, sodium methoxide and sodium ethoxide; the organic acid can be selected from one or the combination of p-toluenesulfonic acid, formic acid and acetic acid.
10. The method according to claim 2, wherein the molar ratio of compound VI to catalyst in step (3) is 1: 1.1-2.0.
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