CN111747929A - Preparation method of topiroxostat - Google Patents

Abstract

The invention provides a preparation method of topiroxostat, which comprises the steps of taking isonicotinic acid as a starting raw material, oxidizing by hydrogen peroxide to obtain isonicotinic acid-nitrogen oxide (an intermediate 1), esterifying by methanol to obtain isonicotinic acid methyl ester-nitrogen oxide (an intermediate 2), hydrazinolyzing by hydrazine hydrate to obtain isonicotinic acid hydrazine-nitrogen oxide (an intermediate 3), reacting with 4-cyanopyridine to obtain an intermediate 4, cyaniding by trimethylsilyl cyanide to obtain an intermediate 5, and finally dehydrating and closing a ring to generate topiroxostat. The method has the advantages that the initial raw materials and various reagents are cheap and easy to obtain; the experimental operation is simple and controllable, the reaction conditions of the electrodeless end are avoided, and the method is suitable for laboratory development and even industrial production; the total yield is higher, and the production cost is reduced; the purity of the finished product is ensured.

Description

Preparation method of topiroxostat

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of topiroxostat.

Background

Gout is a crystal-related arthropathy resulting from the deposition of monosodium urate (MSU) and is directly associated with purine metabolic disorders and/or hyperuricemia resulting from decreased uric acid excretion. With the improvement of living standard of people, the dietary structure is obviously changed, the purine intake is obviously increased, the incidence of hyperuricemia and gout is obviously increased, and the gout has a trend of gradual rejuvenation, and the gout becomes the second major metabolic disease, is second to diabetes and threatens the health of human beings. The drug treatment of gout mainly comprises two aspects, namely controlling the blood uric acid level on one hand and controlling the acute attack of gout on the other hand.

Topiroxostat (topiroxostat), chemical name: 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2, 4-triazole is a xanthine oxidase inhibitor and can effectively inhibit the formation of uric acid. Its inhibitory action is highly selective (a specific inhibitor against xanthine oxidase only), that is, Topiroxostat selects only the enzyme that one wishes to inhibit, has no or little inhibitory effect on other enzymes of the purine and pyrimidine metabolism that exert normal physiological effects, and also does not affect the purine and pyrimidine metabolic synthesis. It has better curative effect and less side effect. Therefore, the research on the synthesis of topiroxostat is more and more focused.

At present, the published synthetic routes reported by topiroxostat mainly include the following routes:

patent CN1561340A, the earliest published synthetic route of topiroxostat, applied in china by fuji drug corporation:

reacting isonicotinic acid-nitrogen oxide with a condensing agent 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline for 1 hour under the protection of argon, reacting with methanol, and purifying by column chromatography to obtain isonicotinic acid methyl ester-nitrogen oxide; secondly, reacting methyl isonicotinate-nitrogen oxide with trimethylsilyl cyanide, and purifying by column chromatography to obtain 2-cyano methyl isonicotinate; and thirdly, reacting with hydrazine hydrate to generate 2-cyanoisoniazid, and finally reacting with 4-cyanopyridine to obtain the finished product of topiroxostat.

The initial raw material isonicotinic acid-nitrogen oxide in the route is few in manufacturers on the market and expensive; a condensing agent is used in the first step of reaction, so that the cost is high; wherein, the multi-step reaction requires column chromatography purification and is difficult to realize industrial production.

Secondly, on the basis of the above-mentioned route, japanese fuji chemical co also discloses another route reported in chinese application patent CN 1826335A:

according to the method, isoniazid and 4-cyanopyridine-nitrogen oxide are used as starting materials, a triazazole ring is firstly closed, then N benzyl protection is carried out, then cyano is introduced, and finally benzyl is removed to obtain a final product topirostat.

One of the starting materials of the route is 4-cyanopyridine oxynitride which is expensive and has small market supply; in the third step, a reagent benzyl chloride is needed, the irritation is strong, and the process cost is increased in the process of protecting and removing the benzyl.

Thirdly, the synthetic route reported in the literature (Tetrahedron letters; vol. 49; nb. 28; (2008); P. 4369-4371):

the method comprises the steps of taking isonicotinic acid-nitrogen oxide as an initial raw material, reacting with ethyl chloroformate to form an active anhydride intermediate, reacting with hydrazine protected by single Boc to generate isonicotinic acid-nitrogen oxide protected by Boc, introducing cyano through trimethylcyanosilane, removing Boc through p-toluenesulfonic acid, and finally, producing the finished product of topiroxostat through 4-cyanopyridine ring closure.

The initial raw material isonicotinic acid-nitrogen oxide in the route has less supply quantity on the market and higher price, the reagent ethyl chloroformate used in the first step is a highly toxic product, and the hydrazine protected by the single Boc used in the second step has higher price and is difficult to be used in industrial production.

Fourthly, another synthetic route is reported in the literature (Tetrahedron letters; vol. 49; nb. 28; (2008); P. 4369-) -4371):

according to the method, isoniazid and 4-cyanopyridine-nitrogen oxide are used as initial raw materials, a triazole ring is firstly closed, then the triazole ring reacts with zinc cyanide, a cyano group is introduced, and finally, p-toluenesulfonic acid is used for removing N-dimethyl acyl to generate topirostane-p-toluenesulfonic acid.

The route is short, the steps are simple, but 4-cyanopyridine oxynitride which is one of the starting raw materials is expensive, and the market supply quantity is small; the second step of the cyanide is zinc cyanide which needs to be used in a large excess amount (3.0 eq), the yield is not high and is about 66%, and the environmental pollution is large.

Disclosure of Invention

The original process routes all have certain defects, and industrial production is difficult to realize. The invention develops a new synthetic route of topiroxostat with higher feasibility, and carries out systematic process optimization on each step of reaction, so that the route can meet the requirements of industrial production.

The reaction route is as follows:

the method specifically comprises the following steps:

the method comprises the following steps: reacting isonicotinic acid serving as a starting material and acetic acid serving as a solvent with hydrogen peroxide at 70-100 ℃, adding acetone for crystallization after the reaction is finished, and filtering to obtain isonicotinic acid-nitrogen oxide (an intermediate 1);

step two: reacting isonicotinic acid-nitrogen oxide (intermediate 1) with methanol under the reflux condition under the catalysis of concentrated sulfuric acid, adjusting to be alkaline by using sodium carbonate after the reaction is finished, filtering, evaporating filtrate to dryness, dissolving by using dichloromethane, washing by using a sodium carbonate solution, and evaporating to dryness again to obtain isonicotinic acid methyl ester-nitrogen oxide (intermediate 2);

step three: reacting methyl isonicotinate-nitrogen oxide (intermediate 2) with hydrazine hydrate under the condition of methanol reflux, and cooling and crystallizing to obtain isonicotinyl hydrazine-nitrogen oxide (intermediate 3) after the reaction is finished;

step four: reacting isoniazid-nitrogen oxide (intermediate 3) with 4-cyanopyridine under reflux conditions by using methanol as a solvent under the catalysis of sodium methoxide; adding water for crystallization after the reaction is finished, and pulping the obtained solid by ethanol to obtain an intermediate 4;

step five: the intermediate 4 reacts with trimethylsilyl cyanide to introduce cyano; after the reaction is finished, adding a sodium bicarbonate aqueous solution for crystallization, washing with water, and leaching with ethanol to obtain an intermediate 5;

step six: under the action of inorganic acid (phosphoric acid, sulfuric acid or polyphosphoric acid), 2-butanol is taken as a solvent, and the target product topiroxostat is generated by ring closure at 80 ℃.

The starting materials of isonicotinic acid, the intermediate reactant 4-cyanopyridine and other reaction reagents and solvents in the route are cheap and easy to obtain. The reaction conditions in each step are mild, the operation is simple, and the controllability is strong. Is suitable for laboratory development and subsequent industrial production. The total yield is 51.4 percent, the refining yield is 91.8 percent, the purity of the refined product reaches 99.82 percent, and the single impurity is less than 0.1 percent.

Drawings

Fig. 1 is a liquid phase spectrum of topiroxostat finished product.

FIG. 2 is a mass spectrum of Topiroxostat finished product liquid.

Fig. 3 is a nuclear magnetic hydrogen spectrum diagram of a topiroxostat finished product.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The invention is further illustrated by the following examples:

example 1, preparation of intermediate 1:

the starting material (20.0 g, 0.16 mol, 1.0 eq) was dissolved in acetic acid (100 mL) at room temperature (ca. 25)^oC) Adding hydrogen peroxide (54.4 g, content 30%, 0.48 mol, 3.0 eq), heating to 90%^oC, reacting for 8 hours. HPLC showed no starting material remaining, the heating was stopped, the temperature was reduced to room temperature, 200 mL of acetone was added, the mixture was crystallized for 1 h, filtered, and the filter cake was rinsed twice with a small amount of acetone (total 100 mL). The obtained solid was dissolved in 45^oAnd C, blowing and drying for 10 hours. Yield 20.91 g of product: 93.9 percent.

Example 2, preparation of intermediate 2:

dissolving intermediate 1 (10.0 g, 71.9 mmol, 1.0 eq) in methanol (80 mL), and adding concentrated sulfuric acid (5.0 g) dropwise while controlling the internal temperature to be not more than 40^oC, heating to an external temperature of 75 DEG^oAnd C, refluxing and reacting for 8 h. TLC shows that the raw materials are not much left, stopping heating, cooling in ice water bath, adding sodium carbonate solid in batches, and controlling the internal temperature to be not more than 20^oAnd C, adjusting the pH value to about 7, filtering, and leaching the filter cake twice with a small amount of methanol. Adding methanol to the solution at 45^oThe solid was dissolved in dichloromethane (100 mL) and washed once with 5% aqueous sodium carbonate (15 mL). Will twoThe chloromethane phase is separated off, dried over a little sodium sulfate and taken up at 45 deg.C^oAnd C, decompressing and evaporating to dryness to obtain 10.10 g of a product, wherein the yield is as follows: 91.2 percent.

Example 3, preparation of intermediate 3:

adding intermediate 2 (12.0 g, 78.4 mmol, 1.0 eq) into methanol (80 mL), adding hydrazine hydrate (80% content, 5.88 g, 94.0 mmol, 1.2 eq), and heating to 70 deg.C^oAnd C, refluxing and reacting for 6 h. TLC showed complete consumption of starting material and the ice-salt bath was cooled to an internal temperature of 5 deg.C^oAnd (4) crystallizing for 2 h within C, filtering, and leaching a filter cake once by using a small amount of methanol (20 mL). The obtained solid was dissolved in 45^oAnd D, blowing and drying for 4 hours under the condition of C to obtain 11.09 g of a product with the yield of 92.4 percent.

Example 4, preparation of intermediate 4:

intermediate 3 (8.20 g, 53.55mmol, 1.0 eq) was added to methanol (65 mL) without dissolution. Sodium methoxide (0.29 g, 5.35 mmol, 0.1 eq), 4-cyanopyridine (6.70 g, 64.3 mmol, 1.2 eq) were added sequentially. Heating to the external temperature of 70^oC, dissolving clear at the moment, refluxing for 5 h, and TLC shows that the reaction is finished and a solid is separated out. Cooling to room temperature, adding water (100 mL), stirring for 20 min, filtering, adding the filter cake into ethanol (80 mL), pulping for 1 h, filtering, and rinsing the filter cake with a small amount of ethanol (20 mL). The obtained solid is dissolved in 50^oAnd C, blowing and drying for 12 hours. Yield 12.2 g of product: 88.5 percent.

Example 5, preparation of intermediate 5:

intermediate 4 (5.0 g, 19.4 mmol, 1.0 eq) was dissolved in DMF (30 mL) and the temperature was controlled between 5-10 deg.C^oDIPEA (5.02 g, 38.9 mmol, 2.0 eq) and TMSCN (2.31 g, 23.3 mmol, 1.2 eq) were added dropwise in that order to the interior of C. Continuously keeping 5-10^oN, N-dimethylcarbamoyl chloride (3.14 g, 29.2 mmol, 1.5 eq) was added dropwise to the reaction mixture over C. Gradually heating to an internal temperature of 45^oC, reacting for 6 h, and HPLC (high performance liquid chromatography) shows that the reaction is finished. The reaction solution is reduced to 10^oAbout C, 5% sodium bicarbonate solution (80 mL) was added, stirred for 30 min, filtered, and the filter cake was rinsed twice with purified water (60 mL). The filter cake was slurried in ethanol (80 mL) for 1 h, filtered, and the filter cake rinsed once with a small amount of ethanol. The obtained solid is dissolved in 50^oAnd C, blowing and drying for 12 hours. Yield 4.50 g of product: 87.1 percent.

Example 6 preparation of a finished topiroxostat product:

at room temperature (25)^oC) Intermediate 5 (6.0 g) was added to 2-butanol (42 mL) and polyphosphoric acid (2.4 g) was added, at which point it was not completely dissolved. Heating to an internal temperature of 80^oC, reacting for 5 hours. TLC showed the reaction was complete, down to 20^oAdding purified water (63 mL) within C, adjusting pH to about 7 with 10% sodium carbonate aqueous solution, and stirring for 30 min. Filtration was performed and the filter cake was rinsed twice with a mixture of 2-butanol and water (2-butanol/water = 1/10) for a total of 30 mL. The solid is dissolved in 50^oAnd C, blowing and drying for 12 hours. Yield 4.72 g of product: 84.3 percent.

Example 7, purification of the final product:

4.0 g of the crude product was added to DMF (24 mL) and the temperature was raised to 60^oC, completely dissolving and stirring for 10 min. Cooled to room temperature (25)^oC) MTBE (72 mL) was added and the mixture was crystallized at room temperature for 2 hours. Filtration, cake washing with a small amount of MTBE (30 mL) twice, and solids at 50%^oAnd C, blowing and drying for 6 hours. Yield 3.67 g of product: 91.8 percent. HPLC purity (area normalization): 99.82 percent.

Claims (2)

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

(1) reacting isonicotinic acid serving as a starting material and acetic acid serving as a solvent with hydrogen peroxide to generate isonicotinic acid-nitrogen oxide (an intermediate 1);

(2) reacting isonicotinic acid-nitrogen oxide (intermediate 1) with methanol under the catalysis of concentrated sulfuric acid to generate isonicotinic acid methyl ester-nitrogen oxide (intermediate 2);

(3) reacting methyl isonicotinate-nitrogen oxide (intermediate 2) with hydrazine hydrate to generate isoniazid-nitrogen oxide (intermediate 3);

(4) reacting isoniazid-nitrogen oxide (intermediate 3) with 4-cyanopyridine under the catalysis of sodium methoxide to generate an intermediate 4;

(5) the intermediate 4 reacts with trimethylsilyl cyanide to introduce cyano to generate an intermediate 5;

(6) and (3) performing ring closure on the intermediate 5 under the action of inorganic acid to generate the target product topiroxostat.

The synthetic route and the process are as follows:

2. the process for preparing topiroxostat according to claim 1, characterized by comprising the following steps:

the method comprises the following steps: reacting isonicotinic acid serving as a starting material and acetic acid serving as a solvent with hydrogen peroxide at 70-100 ℃, adding acetone for crystallization after the reaction is finished, and filtering to obtain isonicotinic acid-nitrogen oxide (an intermediate 1);

step two: reacting isonicotinic acid-nitrogen oxide (intermediate 1) with methanol under the reflux condition under the catalysis of concentrated sulfuric acid, adjusting to be alkaline by using sodium carbonate after the reaction is finished, filtering, evaporating filtrate to dryness, dissolving by using dichloromethane, washing by using a sodium carbonate solution, and evaporating to dryness again to obtain isonicotinic acid methyl ester-nitrogen oxide (intermediate 2);

step three: reacting methyl isonicotinate-nitrogen oxide (intermediate 2) with hydrazine hydrate under the condition of methanol reflux, and cooling and crystallizing to obtain isonicotinyl hydrazine-nitrogen oxide (intermediate 3) after the reaction is finished;

step four: reacting isoniazid-nitrogen oxide (intermediate 3) with 4-cyanopyridine under reflux conditions by using methanol as a solvent under the catalysis of sodium methoxide; adding water for crystallization after the reaction is finished, and pulping the obtained solid by ethanol to obtain an intermediate 4;

step five: the intermediate 4 reacts with trimethylsilyl cyanide to introduce cyano; after the reaction is finished, adding a sodium bicarbonate aqueous solution for crystallization, washing with water, and leaching with ethanol to obtain an intermediate 5;

step six: under the action of inorganic acid (phosphoric acid, sulfuric acid or polyphosphoric acid), 2-butanol is taken as a solvent, and the target product topiroxostat is generated by ring closure at 80 ℃.

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