CN115572747B

CN115572747B - Topiroxostat preparation method

Info

Publication number: CN115572747B
Application number: CN202211170502.XA
Authority: CN
Inventors: 刘卫国; 赵晓娅; 杨毅钢; 黎鸠鸠
Original assignee: Hunan Yige Pharmaceutical Co ltd
Current assignee: Hunan Yige Pharmaceutical Co ltd
Priority date: 2022-09-23
Filing date: 2022-09-23
Publication date: 2023-05-05
Anticipated expiration: 2042-09-23
Also published as: CN115572747A

Abstract

The invention discloses a preparation method of topiroxostat, which comprises the following steps: s1, using 4-cyanopyridine as a starting material, and using sodium hypochlorite as a chlorine source under the action of chloroperoxidase to prepare 2-chloro-4-cyanopyridine; s2, preparing a chlorotriazole compound by taking 2-chloro-4-cyanopyridine and isonicotinyl hydrazide as alkali; s3, reacting the chlorotriazole compound with dimethyl malononitrile in the presence of isopropyl magnesium chloride to prepare topiroxostat. The preparation method of topiroxostat provided by the invention does not need to use extremely toxic chemical reagents, but adopts an enzyme catalysis process, and has mild reaction conditions, good reaction selectivity and high total yield; more importantly, the starting materials are cheap and easy to obtain, and the cost is low; the operability is strong, and the industrialization is easy.

Description

Topiroxostat preparation method

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of topiroxostat.

Background

Topiroxostat (1), chemical name 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2, 4-triazole, is a new generation of anti-hyperuricemia and gout drug developed by Fuji pharmaceutical Co., ltd., three and chemistry, is a non-purine xanthine oxidase inhibitor, has inhibitory effect on both oxidized and reduced xanthine oxidase, inhibits uric acid production, and is marketed in Japan in 2013 at 9 months. Compared with the existing clinically applied anti-gout drugs such as colchicine, nonsteroidal anti-inflammatory drugs and the like, the topiroxostat has the advantages of strong uric acid reducing effect, less adverse reaction, good safety and the like.

At present, the existing synthetic routes of topiroxostat mainly comprise the following steps:

patent CN1561340 filed by fuji pharmaceutical corporation in japan, discloses the synthesis route of topiroxostat at the earliest:

the method comprises the steps of firstly reacting isonicotinic acid-N-oxide with a condensing agent 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline for 1 hour under the protection of argon, then reacting with methanol, and purifying by column chromatography to obtain isonicotinic acid methyl ester nitrogen oxide; secondly, reacting methyl isonicotinate-nitrogen oxide with trimethylsilylcyanide, and obtaining 2-cyano isonicotinate through column chromatography; thirdly, reacting with hydrazine hydrate to obtain 2-cyano isoniazid; finally, the target compound topiroxostat can be obtained after a long time of reaction with 4-cyanopyridine. The process route has long reaction time, needs to use column chromatography for product purification, and particularly in the third step of synthesis, more byproducts A are inevitably generated, industrialization is difficult, expensive and highly toxic trimethylsilicon cyanide is used in the cyanation reaction, the operation danger coefficient is high, and the environmental protection pressure is high.

Another route, which is publicly reported by japanese fuji pharmaceutical corporation, is also disclosed by patent CN1826335 on the basis of the above route:

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firstly, adopting isonicotinyl hydrazide and isonicotinyl nitrile-N-oxide to react to prepare triazole, then protecting the triazole compound, then using trimethylcyanogen to carry out cyanation reaction, then deprotecting, and neutralizing p-toluenesulfonic acid with sodium bicarbonate to obtain topiroxostat. The process has the advantages of more steps, low total yield and high cost; and the method also uses expensive and highly toxic trimethyl silicon cyanide, and has high dangerous coefficient of industrial production operation and high environmental protection pressure.

Document (Tetrahedron Letters 20088 vol.49 (28) 4369-71) reports a similar process route to patent CN 1561340:

the process route has more synthesis steps, particularly, the protection step is firstly carried out and then the deprotection is carried out, and the process is inevitably carried out by using extremely toxic and expensive trimethyl silicon cyanide, so that the cost is higher and the operation difficulty is high.

Chinese patent CN103724329 discloses a unique process route to avoid the use of highly toxic cyano compounds:

in the process route, the yield of the first step of carbamylation is lower and is less than 40%; in the transesterification of methyl ester and hydrazine hydrate, more by-product A is inevitably generated; in the process of generating cyano by amide dehydration, the dosage of the dehydrating agent is large, the environment-friendly pressure is high, the corrosiveness to instruments and equipment is high, and the industrialization difficulty is high.

Disclosure of Invention

The invention provides a preparation method of topiroxostat, which aims to solve the technical problems of high operation difficulty and difficult mass production caused by the fact that extremely toxic or corrosive raw materials are needed in the existing preparation method.

In order to achieve the above purpose, the invention provides the following technical scheme:

a method for preparing topiroxostat, comprising the following steps:

s1, using 4-cyanopyridine as a starting material, and using sodium hypochlorite as a chlorine source under the action of chloroperoxidase to prepare 2-chloro-4-cyanopyridine;

s2, preparing a chlorotriazole compound by taking 2-chloro-4-cyanopyridine and isonicotinyl hydrazide as alkali;

s3, reacting a chlorotriazole compound with dimethyl malononitrile in the presence of isopropyl magnesium chloride to prepare topiroxostat;

the synthetic route is as follows:

further, in step S1, the reaction solvent is disodium hydrogen phosphate; and/or the reaction temperature is 0-40 ℃; the reaction time is 5-48 h.

Further, in step S1, the weight ratio of the compound 4-cyanopyridine to chloroperoxidase is (5 to 25): 1.

further, in step S1, in S1, the molar ratio of 4-cyanopyridine to sodium hypochlorite is 1: (1-15).

Further, in step S2, the reaction solvent is methanol; and/or the reaction temperature is 20-80 ℃; the reaction time is 4-30 h.

Further, in step S2, the molar ratio of 2-chloro-4-cyanopyridine to isonicotinyl hydrazide is 1: (0.8-2).

Further, in step S2, the molar ratio of 2-chloro-4-cyanopyridine to sodium methoxide is (10 to 100): 1.

further, in step S3, the reaction solvent is tetrahydrofuran; and/or the reaction temperature is-10 to 40 ℃; the reaction time is 0.5-8 h.

Further, in step S3, the molar ratio of the chlorotriazole compound to isopropyl magnesium chloride is 1: (0.8-3.0).

Further, in step S3, the molar ratio of the chlorotriazole compound to the dimethylmalononitrile is 1: (0.8-3.0).

The invention has the following beneficial effects:

in the step S1 of the preparation method of topiroxostat, 4-cyanopyridine is used as a starting material, sodium hypochlorite is used as a chlorine source under the action of chloroperoxidase to prepare 2-chloro-4-cyanopyridine, the yield of the 2-chloro-4-cyanopyridine is 91.1-94.1%, and the purity is 98.2-98.6%;

in the step S2, 2-chloro-4-cyanopyridine and isonicotinyl hydrazide are subjected to alkali treatment by sodium methoxide to prepare a chlorotriazole compound, wherein the yield of the chlorotriazole compound is 89.4-91.9%, and the purity is 98.2-98.6%;

in the step S3, the chlorotriazole compound reacts with the dimethyl malononitrile in the presence of isopropyl magnesium chloride to prepare the topiroxostat, wherein the yield of the topiroxostat is 89.7-91.4% and the purity is 99.1-99.4%.

The preparation method of topiroxostat provided by the invention does not need to use extremely toxic chemical reagents (such as sodium cyanide, trimethylsilicon cyanide and the like), but adopts an enzyme catalysis process, and has the advantages of mild reaction conditions, good reaction selectivity and high total yield; more importantly, the starting materials are cheap and easy to obtain, and the cost is low; the operability is strong, and the industrialization is easy.

Detailed Description

In order to make the objects, technical solutions and advantageous technical effects of the present invention clearer, the present invention will be further described in detail with reference to examples. It should be understood that the examples described in this specification are for the purpose of illustrating the invention only and are not intended to limit the invention.

For simplicity, only a few numerical ranges are explicitly disclosed herein. However, any lower limit may be combined with any upper limit to form a range not explicitly recited; and any lower limit may be combined with any other lower limit to form a range not explicitly recited, and any upper limit may be combined with any other upper limit to form a range not explicitly recited. Furthermore, each point or individual value between the endpoints of the range is included within the range, although not explicitly recited. Thus, each point or individual value may be combined as a lower or upper limit on itself with any other point or individual value or with other lower or upper limit to form a range that is not explicitly recited.

In the description herein, unless otherwise indicated, "above" and "below" are intended to include the present number, "one or more" means two or more, and "one or more" means two or more.

The embodiment of the application provides a preparation method of topiroxostat, which comprises the following steps:

the synthetic route is as follows:

In the embodiment of the application, the reaction temperature of the step S1 is 0-40 ℃, preferably 10-30 ℃, and most preferably 20-28 ℃; the reaction time is 5 to 48 hours, preferably 18 to 30 hours.

In the step S1, the weight ratio of the compound 4-cyanopyridine (2) to the chloroperoxidase is (5-25): 1, preferably the weight ratio is (10-15): 1.

in step S1, the molar ratio of the compound 4-cyanopyridine to sodium hypochlorite (12% aqueous solution) is 1: (1-15), preferably the molar ratio is 1: (2-5).

In step S1, the reaction solvent is disodium hydrogen phosphate, and the pH of the disodium hydrogen phosphate is 4.2.

After the reaction, the pH value of the reaction solution is adjusted to about 9.5 by using a 2N (2 mol/L) sodium hydroxide solution, the product is extracted by using isopropyl acetate, an organic phase is separated, part of the organic solvent is concentrated under reduced pressure, the temperature is slowly reduced to minus 5 ℃, crystallization is carried out, filtration is carried out, and then the off-white solid 2-chloro-4-cyanopyridine (3) is obtained by vacuum drying at 30-40 ℃.

The reaction temperature in the step S2 is 20-80 ℃, and the preferable temperature is 55-65 ℃; the reaction time is 4 to 30 hours, preferably 8 to 14 hours.

In step S2, the molar ratio of 2-chloro-4-cyanopyridine (3) to isonicotinyl hydrazide (4) is 1: (0.8 to 2), preferably in a molar ratio of 1: (0.9-1.2).

In the step S2, the molar ratio of the 2-chloro-4-cyanopyridine (3) to the sodium methoxide is (10-100): 1, preferably in a molar ratio of (20 to 40): 1.

the reaction solvent in the step S2 is methanol, after the reaction is finished, the reaction is slowly cooled to room temperature, filtered, washed by water and 50% methanol water solution, and then dried in vacuum at 50-55 ℃ to obtain light yellow solid 2-chloro-4- [ (5-pyridin-4-yl-1H- [1,2,4] triazol-3-yl ] -pyridine, namely the chlorotriazole compound (5).

The reaction temperature in the step S3 is-10-40 ℃, and the preferable temperature is 15-25 ℃; the reaction time is 0.5 to 8 hours, preferably 1 to 3 hours.

In step S3, the molar ratio of the chlorotriazole compound (5) to isopropyl magnesium chloride is 1: (0.8 to 3.0), preferably in a molar ratio of 1: (0.9-2), more preferably 1 (1.2-1.6).

In step S3, the molar ratio of the chlorotriazole compound (5) to the dimethylmalononitrile is 1: (0.8 to 3.0), preferably 1 (1.2 to 1.5).

The reaction solvent in the step S3 is Tetrahydrofuran (THF), after the reaction is finished, saturated ammonium chloride solution is slowly added to quench the reaction, an organic phase is separated, then ethyl acetate is used for extracting the product in the aqueous phase, the organic phase is combined, sodium sulfate is used for drying the organic phase, a small amount of active carbon is added for decoloring, sodium sulfate and active carbon are filtered after drying and decoloring, part of the organic solvent is concentrated under reduced pressure, the temperature is reduced to 15 ℃, crystallization is carried out, filtration is carried out, a small amount of ethyl acetate is used for leaching, and then vacuum drying is carried out at 35-45 ℃ to obtain the light yellow solid topiroxostat (1) as a final product.

The reaction formulas of step S1 to step S3 are as follows:

examples

The following examples more particularly describe the disclosure of the present application, which are intended as illustrative only, since numerous modifications and variations within the scope of the disclosure will be apparent to those skilled in the art. Unless otherwise indicated, all parts, percentages, and ratios reported in the examples below are by weight, and all reagents used in the examples are commercially available or were obtained synthetically according to conventional methods and can be used directly without further treatment, as well as the instruments used in the examples.

Example 1

500g of 4-cyanopyridine is added into 4kg of sodium dihydrogen phosphate buffer solution with pH of 4.2, 50g of chloroperoxidase is added after stirring, dissolving and clarifying, 14.8kg of 12% sodium hypochlorite solution is slowly added dropwise at the temperature of 28 ℃ after 4 hours, the pH is regulated to about 9.5 by using 2N sodium hydroxide solution after the completion of the dropwise addition, 4kg of isopropyl acetate is added for extraction, part of organic solvent is concentrated under reduced pressure, the temperature is slowly reduced to-5 ℃ for crystallization, filtration is carried out, and then 623.6g of white solid like 2-chloro-4-cyanopyridine (3) is obtained after vacuum drying at the temperature of 30-40 ℃, and the yield is 94.0% and the purity is 98.2%.

623.6g of 2-chloro-4-cyanopyridine is dissolved in 4kg of methanol, 742.9g of isonicotinyl hydrazide and 12.2g of sodium methoxide are added, stirred at room temperature for 1 hour, reacted at 65 ℃ for 8 hours, then slowly cooled to room temperature, filtered, rinsed with drinking water and 50% aqueous methanol solution, and then dried under vacuum at 50-55 ℃ to obtain 1.06kg of pale yellow solid 2-chloro-4- [ (5-pyridin-4-yl) -1H- [1,2,4] triazol-3-yl ] -pyridine (5), yield 91.3% and purity 98.6%.

1.06kg of 2-chloro-4- [ (5-pyridin-4-yl) -1H- [1,2,4] triazol-3-yl ] -pyridine is dissolved in 7kg of tetrahydrofuran, 3.29L of 2mol/L isopropyl Grignard reagent is slowly added when the temperature of the solution is reduced to 0 ℃, after 1.5 hours of reaction at 0 ℃, a tetrahydrofuran solution of dimethyl malononitrile is slowly added (581.6 g of dimethyl malononitrile is dissolved in 2kg of tetrahydrofuran), after that, the solution is slowly increased to 25 ℃ and reacted for 1 hour at 25 ℃, a proper amount of saturated ammonium chloride solution is slowly added to quench the reaction, an organic phase is separated, then 2kg of ethyl acetate is used for extracting the product in the aqueous phase, the organic phase is combined, the organic phase is dried by sodium sulfate, a small amount of active carbon is added for decolorization, sodium sulfate and active carbon are filtered after the decolorization, about 4kg of organic solvent is reduced in pressure and concentrated to 15 ℃, crystallization is carried out, leaching is carried out, then the leaching is carried out by ethyl acetate, and then the product is dried at 35 ℃ for 1.45 ℃ under vacuum, and the light yellow solid with purity of 374% of which is 99.7% of the product is obtained.

Example 2

1kg of 4-cyanopyridine is added into 8.5kg of sodium dihydrogen phosphate buffer solution with pH of 4.2, 67g of chloroperoxidase is added after stirring, dissolving and clarifying, 11.9kg of 12% sodium hypochlorite solution is slowly added dropwise at 20 ℃ for 4.5 hours, the pH is regulated to about 9.5 by using 2N sodium hydroxide solution after the dropwise addition is completed, 8kg of isopropyl acetate is added for extraction, part of organic solvent is concentrated under reduced pressure, the temperature is slowly reduced to-5 ℃, crystallization is carried out, filtering is carried out, and then vacuum drying is carried out at 30-40 ℃ to obtain 1.25kg of white solid-like 2-chloro-4-cyanopyridine (3), the yield is 94.2%, and the purity is 98.3%.

1.25kg of 2-chloro-4-cyanopyridine is dissolved in 7.8kg of methanol, 1.12kg of isonicotinyl hydrazide and 12.3g of sodium methoxide are added, after stirring for 1 hour at room temperature, the mixture is reacted for 14 hours at 55 ℃ under temperature control, then the mixture is slowly cooled to room temperature, filtered, leached by drinking water and 50% of methanol aqueous solution, and then dried in vacuum at 50-55 ℃ to obtain 2.08kg of light yellow solid 2-chloro-4- [ (5-pyridin-4-yl) -1H- [1,2,4] triazol-3-yl ] -pyridine (5), the yield is 89.4%, and the purity is 98.4%.

1.98kg of 2-chloro-4- [ (5-pyridin-4-yl) -1H- [1,2,4] triazol-3-yl ] -pyridine was dissolved in 13.9kg of tetrahydrofuran, 4.62L of 2mol/L isopropyl Grignard reagent was slowly added when the temperature of the solution was lowered to 0 ℃, after 1.5 hours of reaction at 0 ℃, a tetrahydrofuran solution of dimethyl malononitrile (869.1 g of dimethyl malononitrile was dissolved in 3kg of tetrahydrofuran), after that, the addition was completed, slowly raised to 25 ℃ and reacted at 15 ℃ for 3 hours, a proper amount of saturated ammonium chloride solution was slowly added to quench the reaction, an organic phase was separated, the product in the aqueous phase was extracted with 3.5kg of ethyl acetate, the organic phase was combined, dried with sodium sulfate, and a small amount of active carbon was added to decolorize, after the drying and decolorization, sodium sulfate and active carbon were filtered off, about 7.5kg of organic solvent was reduced in pressure, crystallization was carried out to 15 ℃, leaching was carried out, and then a pale yellow solid (1.74% of solid was obtained after the leaching, a small amount of ethyl acetate was dried at 35 ℃ under vacuum).

Example 3

3kg of 4-cyanopyridine is added into 24kg of sodium dihydrogen phosphate buffer solution with pH of 4.2, after stirring, dissolving and clarifying, 240g of chloroperoxidase is added, 44.5kg of 12% sodium hypochlorite solution is slowly added dropwise at 25 ℃ for 5 hours, after the dropwise addition is completed, the pH is regulated to about 9.5 by using 2N sodium hydroxide solution, 20kg of isopropyl acetate is added for extraction, part of organic solvent is concentrated under reduced pressure, and the temperature is slowly reduced to-5 ℃ for crystallization, filtration is carried out, and then 3.72kg of white solid like 2-chloro-4-cyanopyridine (3) is obtained by vacuum drying at 30-40 ℃, the yield is 91.1%, and the purity is 98.6%.

3.72kg of 2-chloro-4-cyanopyridine was dissolved in 22kg of methanol, 3.69g of isonicotinyl hydrazide and 48.5g of sodium methoxide were added, stirred at room temperature for 1 hour, then reacted at 60℃for 12 hours, then slowly cooled to room temperature, filtered, rinsed with drinking water and 50% aqueous methanol solution, and then dried under vacuum at 50-55℃to obtain 6.37kg of 2-chloro-4- [ (5-pyridin-4-yl) -1H- [1,2,4] triazol-3-yl ] -pyridine (5) as a pale yellow solid, the yield was 91.9%, and the purity was 98.2%.

6.37kg of 2-chloro-4- [ (5-pyridin-4-yl) -1H- [1,2,4] triazol-3-yl ] -pyridine is dissolved in 35kg of tetrahydrofuran, 17.4L of 2mol/L isopropyl Grignard reagent is slowly added when the temperature of the solution is reduced to 0 ℃, after 1.5 hours of reaction at 0 ℃, a tetrahydrofuran solution of dimethyl malononitrile (3.15 kg of dimethyl malononitrile is dissolved in 9kg of tetrahydrofuran) is slowly added, after that, the solution is slowly increased to 20 ℃ and reacted for 2 hours at 20 ℃, a proper amount of saturated ammonium chloride solution is slowly added to quench the reaction, an organic phase is separated, the product in the aqueous phase is extracted by 11kg of ethyl acetate, the organic phase is combined, dried by sodium sulfate, a small amount of active carbon is added for decolorization, sodium sulfate and active carbon are filtered off, about 22kg of organic solvent is concentrated under reduced pressure after the drying and decolorization, crystallization is carried out at 15 ℃, leaching is carried out, then the leaching is carried out by ethyl acetate, and after the leaching is carried out for 2 hours, a proper amount of saturated ammonium chloride solution is slowly added, the organic solvent is slowly added, the pale yellow solid is obtained, and the pale yellow solid with purity of 1.91% of which is 1.91% of purity at 45% and is obtained by vacuum at 45 kg of 5.5%.

While the present application has been described with reference to a preferred embodiment, various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the present application, and in particular, the technical features mentioned in the various embodiments may be combined in any manner as long as there is no structural conflict. The present application is not limited to the specific embodiments disclosed herein, but encompasses all technical solutions falling within the scope of the claims.

Claims

1. The preparation method of topiroxostat is characterized by comprising the following steps:

in the step S1, the reaction solvent is disodium hydrogen phosphate; and/or the reaction temperature is 0-40 ℃; the reaction time is 5-48 h;

in the step S1, the weight ratio of the compound 4-cyanopyridine to the chloroperoxidase is (5-25): 1, a step of;

in step S1, the molar ratio of 4-cyanopyridine to sodium hypochlorite is 1: (1-15);

in step S2, the reaction solvent is methanol; and/or the reaction temperature is 20-80 ℃; the reaction time is 4-30 h;

in step S2, the molar ratio of 2-chloro-4-cyanopyridine to isonicotinyl hydrazide is 1: (0.8-2);

in the step S2, the molar ratio of the 2-chloro-4-cyanopyridine to the sodium methoxide is (10-100): 1, a step of;

in step S3, the reaction solvent is tetrahydrofuran; and/or the reaction temperature is-10-40 ℃; the reaction time is 0.5-8 h;

in step S3, the molar ratio of the chlorotriazole compound to the isopropyl magnesium chloride is 1: (0.8 to 3.0);

in step S3, the molar ratio of the chlorotriazole compound to the dimethylmalononitrile is 1: (0.8 to 3.0);

the synthetic route is as follows:

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