CN115925682A - Topiroxostat synthesis method - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of topiroxostat, which comprises the following steps: 1) Reacting the compound 1 with ammonium sulfide in an imidazole salt aqueous solution to prepare a compound 2; 2) Under the protection of inert gas, reacting the compound 2 with methyl iodide to prepare a compound 3; 3) Reacting the compound 3, the compound 4 and silica gel under microwave irradiation to prepare a compound 5; 4) Reacting the compound 5 with trifluoroacetic anhydride to prepare topiroxostat;
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthetic method of topiroxostat.
Background
Hyperuricemia is a disease caused by disturbance of Uric Acid (UA) metabolism due to various genetic and environmental factors, and is characterized by abnormal rise of urate level in serum, exceeding the solubility limit at physiological temperature and pH (about 6.8 mg/dL), and formation of microcrystals in joint capillaries, resulting in gout. At present, in clinical practice, the medicine mainly treats gout by inhibiting the generation of UA, reduces the activity of Xanthine Oxidase (XOR), inhibits the conversion of hypoxanthine into xanthine, further reduces the generation of UA and reduces the concentration of UA in blood.
Topiroxostat (topiroxostat) is a novel XOR inhibitor, is developed by Fuji Yakuhin company and Sanwa Kagaku company in combination, is approved by Japan to be marketed in 6 months in 2013, is used for treating hyperuricemia of patients with gout or non-gout patients, has good tolerance and small adverse reaction, and is one of the most effective medicaments for treating gout at present.
Topiroxostat, chemical name 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2, 4-triazole, molecular weight: 248.24, CAS number: 577778-58-6, formula: c 13 H 8 N 6 . The structural formula is as follows:
topiroxostat is formed by splicing triazole ring fragments and two pyridine ring fragments, and the synthetic patents can be simply summarized into three types: firstly, introducing cyano (or directly taking a 2-cyanopyridine derivative as a starting material) at the 2-position of pyridine, and then constructing a triazole ring (the splicing of the pyridine ring and the construction of the triazole ring can be completed in one pot); one is that triazole ring is firstly constructed (the splicing of pyridine ring and the construction of triazole ring can be completed by one pot), and then cyano is introduced into pyridine 2-position; the other type is that two pyridine rings are spliced firstly, then cyano is introduced into the 2-position of pyridine, and finally the triazole ring is constructed by closing the ring to obtain the final product.
Patent CN1561340A reports the first synthetic route of topiroxostat: the method comprises the following steps of taking isonicotinic acid-N-oxide (2) as an initial raw material, firstly carrying out esterification reaction with methanol, then reacting with Trimethylcyanosilane (TMSCN) to obtain 2-cyano isonicotinic acid methyl ester (4), then carrying out hydrazinolysis reaction with hydrazine hydrate to obtain 2-cyano isonicotinic acid hydrazine (5), and finally carrying out ring-closing reaction with 4-cyanopyridine (6) to obtain a product 1. The synthetic route is shown as the following formula. In the synthesis method, the starting materials 2 and TMSCN are expensive (the latter is highly toxic), the reaction time of the first two steps is too long, and column chromatography is required. Furthermore, the overall yield of this route is only 14.8%, which is suitable for the small-batch preparation of the target compound. Thus, it is difficult to apply the method to industrial production.
In patent CN10372432329A, methyl isonicotinate (12) is used as an initial raw material, and firstly, amidation reaction is performed under the action of formamide, concentrated sulfuric acid, ferrous sulfate heptahydrate and 30% hydrogen peroxide, and compound 4 is prepared by cyanuric chloride dehydration; then, carrying out hydrazinolysis reaction on the 4 and hydrazine hydrate to obtain 5; finally, 5 and 6 undergo a ring closure reaction to obtain a product 1. The synthetic route is shown as the following formula. The total yield of the four-step reaction in the route is only 11.7%, the process is complicated (in the first step of reaction, ferrous sulfate heptahydrate and 30% hydrogen peroxide are added alternately for multiple times, the requirement on equipment is high, and the post-treatment process is complicated), and the method is not suitable for industrial production.
In patent CN1826335A, isoniazid (17) is used as starting material, and firstly, the isoniazid and 4-cyanopyridine-N-oxide (18) undergo a ring closure reaction to obtain a product 19; then, introducing a protecting group on the triazole ring NH of 19 to obtain a compound 20;20, carrying out cyanidation reaction under the action of TMSCN and DMCI to obtain a product 21;21 reacting with paratoluenesulfonic acid monohydrate in IPA to obtain a deprotected product 14; finally, reaction of 14 with sodium bicarbonate dissociates the salt to give product 1. The synthetic route is shown as the following formula. The steps of the route are complicated, the solubility of the intermediate is poor, a large amount of solvent is required for extraction and washing, and the cost is increased; the reaction time is long, and impurities such as p-toluenesulfonic acid ester can be generated by refining the p-toluenesulfonic acid monohydrate; meanwhile, the cyano group is introduced by using the highly toxic cyanide TMSCN, so that the environmental protection pressure is high, and the industrial production is not facilitated.
In patent CN104411686A, 4-cyanopyridine-N-oxide (18) is used as a starting material, and condensation reaction between 18 and isoniazid (17) occurs in a sodium methoxide/methanol system to obtain compound 27; carrying out cyanation reaction on 27 in DMF under the action of sodium cyanide and DMCl to obtain 11;11 in a 2-butanol/water system and phosphoric acid to generate ring closing reaction to obtain a product 1. The synthetic route is shown as the following formula. In the second step of the reaction of the route, virulent sodium cyanide is used as a cyanogen source, and the two intermediates 27 and 11 have high polarity, poor fat solubility and difficult separation and purification; the ring-closing reaction adopts phosphoric acid as a condensing agent, and needs to react for a long time at high temperature, so that the yield is low; the cyano group generates side reaction under the combined action of phosphoric acid and trace moisture in the reagent to generate impurity C and impurity D which are difficult to remove, and the requirement of medicine quality is difficult to achieve. Therefore, the process lacks competitiveness in industrial production.
Patent CN107531677A uses 2-carbamoyl-4-cyano-pyridine (3) as substrate, and reacts with isoniazid (5) in sodium methoxide/methanol system through intermediate 6 to obtain product 7; compound 7 was reacted with TFAA/TEA in THF solvent to yield topiroxostat TFA salt, which was finally de-salted by potassium carbonate to give product 1. The synthetic route is shown as the following formula. The ring closing reaction of the route adopts methanol as a solvent, and needs to be carried out for a long time at high pressure and high temperature, so that the risk is high; in the preparation process of the product 1, the distillation of trifluoroacetic acid/trifluoroacetic anhydride is involved, the requirement on equipment is high, the post-treatment process is more complicated, and the industrial production is not facilitated.
The above mentioned methods have significant drawbacks. Patents CN1826335A, CN104411686A use cyanide species for the introduction of cyano groups on pyridine moieties. Such agents must be handled with particular care, since they hydrolyze to produce hydrogen cyanide, an extremely toxic chemical compound. On the other hand, patent CN1561340A uses expensive starting materials and has low yield. In addition, patent CN107531677A has high requirements on equipment, long reaction time and complicated post-treatment process. Aiming at the defects, the invention aims to provide a synthetic route suitable for industrial production of topiroxostat. In the route, the raw materials are widely supplied, and other reagents are low in price, so that certain cost advantage is achieved; successfully avoids using a virulent cyaniding reagent, has simple and convenient post-treatment operation, mild reaction conditions and high safety.
Disclosure of Invention
Aiming at the problems of severe toxic cyaniding reagent, harsh reaction conditions, longer process route, higher raw material cost, lower yield and the like in the prior topiroxostat preparation process. The invention provides a method suitable for industrial production of topiroxostat.
A synthetic method of topiroxostat specifically comprises the following steps:
1) Reacting the compound 1 with ammonium sulfide in an imidazole salt aqueous solution to prepare a compound 2;
2) Under the protection of inert gas, reacting the compound 2 with methyl iodide to prepare a compound 3;
3) Reacting the compound 3, the compound 4 and silica gel under microwave irradiation to prepare a compound 5;
4) Reacting the compound 5 with trifluoroacetic anhydride to prepare topiroxostat;
preferably, the molar ratio of the compound 1 to the ammonium sulfide in step 1) is 1.
Preferably, the imidazolium salt in step 1) is selected from C 6 (mim) 2 Cl 2、 C 4 (mim) 2 Cl 2、 C 8 (mim) 2 Cl 2 One kind of (1).
Further preferably, the imidazolium salt in step 1) is C 6 (mim) 2 Cl 2 。
Preferably, the preparation method of the imidazole salt comprises the following steps: adding 1-methylimidazole to (CH) 2 )nCl 2 Heating for reaction, cooling to room temperature, adding acetone, stirring, vacuum filtering, washing filter cake with acetone, and vacuum drying to obtain Cn (min) 2 Cl 2 Wherein (CH) 2 )nCl 2 Wherein n can be 4, 6,8。
Further preferably, the reaction temperature in the preparation method of the imidazolium salt is 120-140 ℃.
Further preferably, the 1-methylimidazole is bonded to the (CH) in the process for preparing the imidazole salt 2 )nCl 2 In a molar ratio of 2.0 to 2.5:1.
preferably, the imidazole salt can be recycled, and the recycling method comprises the following steps: washing the filtrate reacted in the step 1) with diethyl ether for 3 times, combining organic phases, removing the solvent by vacuum reduced pressure distillation, and drying in vacuum to obtain the imidazole salt.
Preferably, the imidazolium salt can be reused 3 to 5 times without loss of its activity.
Preferably, the molar ratio of the compound 1 to the imidazolium salt in step 1) is 1.
Preferably, the reaction temperature in step 1) is 65 to 75 ℃.
Preferably, the molar ratio of the compound 2 to methyl iodide in the step 2) is 1.
Preferably, the solvent used in step 2) is one or more selected from acetone, ethyl acetate and tetrahydrofuran.
Preferably, the reaction temperature in step 2) is 40 to 55 ℃.
Preferably, the inert gas in step 2) is selected from one of nitrogen and argon.
Preferably, the molar ratio of the compound 3 to the compound 4 in the step 3) is 1.
Preferably, the mass ratio of the compound 3 to the silica gel in the step 3) is 1.8 to 2.5, and more preferably 1.
Preferably, the power of the microwave irradiation in step 3) is 800 to 1000W, more preferably 900W.
Preferably, the microwave irradiation time in step 3) is 10-20 min.
Preferably, step 3) further comprises a post-processing step: soaking and washing the reacted mixture with a deionized water/triethylamine mixed solution, combining washing liquids, distilling and removing the solvent under vacuum, recrystallizing the residue with water/methanol, and drying the obtained solid under vacuum to obtain the compound 5.
Preferably, the mass-to-volume ratio of the compound 5 to the trifluoroacetic anhydride in the step 4) is 1.5 to 3.0, wherein the mass is g and the volume is mL.
Preferably, the reaction in step 4) specifically comprises the following steps: adding the compound 5 into tetrahydrofuran, dropwise adding triethylamine, cooling, dropwise adding trifluoroacetic anhydride, and heating to room temperature for reaction after dropwise adding.
Preferably, the temperature reduction temperature is-5 to 5 ℃.
Compared with the prior art, the invention has the following beneficial effects:
(1) The used reagent is low in price and has cost advantage;
(2) Avoiding the use of a virulent cyaniding reagent;
(3) The post-treatment operation is simple and convenient, the reaction condition is mild, and the safety is high.
Drawings
Fig. 1 topiroxostat PXRD powder diffractogram.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications obvious to those skilled in the art according to the present invention are also included in the scope of the present invention.
Example 1
C 6 (mim) 2 Cl 2 Preparation of (2)
1-methylimidazole (18.0 g, 0.22mol) was added to 1, 6-dichlorohexane (15.5 g, 0.1mol), heated at 120 ℃ for 48 hours, and then cooled to room temperature. Adding acetone (30 mL), stirring for 10 min, vacuum filtering to obtain filter cake, washing with acetone (10 mL), and vacuum drying to obtain C 6 (mim) 2 Cl 2 (28.1 g, yield 88.3% based on 1, 6-dichlorohexane) was used directly in the next reaction.
Compounds 1 (7.4g, 50mmol) and C 6 (mim) 2 Cl 2 (17.5g, 55mmol) was added to a 20% ammonium sulfide (20.4 g, 60mmol) aqueous solution, and the mixture was heated to 65 to 70 ℃ and reacted for 1 to 2 hours with stirring. After completion of the reaction monitored by TLC, deionized water (200 mL) was added to the reaction solution, stirred for 10 minutes, filtered to give a filter cake, recrystallized from ethanol, and dried in vacuo to give compound 2 (8.0 g, yield 88.4%) with HPLC purity of 98.76%.
C 6 (mim) 2 Cl 2 Is recycled and reused
Washing the filtrate with diethyl ether for 3 times, distilling off the solvent under vacuum, and vacuum drying to obtain C 6 (mim) 2 Cl 2 And can be reused four times without loss of activity.
Example 2
C 4 (mim) 2 Cl 2 Preparation of
1-methylimidazole (16.4g, 0.20mol) was added to 1, 4-dichlorobutane (12.7g, 0.1mol), and after heating at 120 ℃ for 48 hours, it was cooled to room temperature. Adding acetone (30 mL), stirring for 10 min, vacuum filtering to obtain filter cake, washing with acetone (10 mL), and vacuum drying to obtain C 4 (mim) 2 Cl 2 (25.5 g, yield 87.5%) was used directly in the next reaction.
Compounds 1 (7.4g, 50mmol) and C 4 (mim) 2 Cl 2 (14.6 g, 50mmol) is added into 20 percent ammonium sulfide (18.7 g, 55mmol) water solution, the temperature is raised to 70-75 ℃, and the reaction is stirred for 1-2 hours. After the completion of the reaction monitored by TLC, deionized water (200 mL) was added to the reaction solution, stirred for 10 minutes, filtered under suction to give a filter cake, recrystallized from ethanol, and dried under vacuum to give compound 2 (7.9 g, yield 87.2%) with HPLC purity of 98.85%.
C 4 (mim) 2 Cl 2 Is recycled and reused
Washing the filtrate with diethyl ether for 4 times, distilling off the solvent under vacuum, and vacuum drying to obtain C 4 (mim) 2 Cl 2 And can be reused four times without loss of activity.
Example 3
C 8 (mim) 2 Cl 2 Preparation of
1-methylimidazole (16.4g, 0.20mol) was added to 1, 8-dichlorooctane (14.6g, 0.08mol), and the mixture was heated at 130 ℃ for 36 hours and then cooled to room temperature. Adding acetone (30 mL), stirring for 10 min, vacuum filtering to obtain filter cake, washing with acetone (10 mL), and vacuum drying to obtain C 8 (mim) 2 Cl 2 (24.2 g, yield 87.2% based on 1, 8-dichlorooctane) was used in the next reaction as it was.
Compound 1 (7.4g, 50mmol) and C 8 (mim) 2 Cl 2 (20.8g, 60mmol) was added to a 20% ammonium sulfide (23.8 g,70 mmol) aqueous solution, the temperature was raised to 70 to 75 ℃ and the reaction was stirred for 1 to 2 hours. After completion of the reaction monitored by TLC, deionized water (200 mL) was added to the reaction solution, stirred for 10 minutes, filtered with suction to give a filter cake, recrystallized from ethanol, and dried in vacuo to give compound 2 (7.8 g, yield 86.3%) with HPLC purity of 98.62%.
C 8 (mim) 2 Cl 2 Is recycled and reused
Washing the filtrate with diethyl ether for 5 times, distilling off the solvent under vacuum, and vacuum drying to obtain C 8 (mim) 2 Cl 2 And can be reused for 5 times without losing the activity.
Example 4
C 2 (mim) 2 Cl 2 Preparation of (2)
1-methylimidazole (16.4g, 0.20mol) was added to 1, 2-dichloroethane (9.9g, 0.1mol), and after heating at 80 ℃ for 48 hours, it was cooled to room temperature. Adding acetone (30 mL), stirring for 10 min, vacuum filtering to obtain filter cake, washing with acetone (10 mL), and vacuum drying to obtain C 2 (mim) 2 Cl 2 (21.6 g, yield 82.2% based on 1, 2-dichloroethane) was used directly in the next reaction.
Compound 1 (7.4g, 50mmol) and C 2 (mim) 2 Cl 2 (17.4g, 70mmol) is added into 20 percent of ammonium sulfide (27.2 g, 80mmol) water solution, the temperature is raised to 50 to 55 ℃, and the reaction is stirred for 1 to 2 hours. After TLC monitoring reaction is completed, deionized water (200 mL) is added into the reaction solution, stirring is carried out for 10 minutes, suction filtration is carried out to obtain a filter cake, and ethanol is added into the filter cakeCrystals were dried in vacuo to give compound 2 (7.3 g, 81.0% yield) with an HPLC purity of 95.43%.
C 2 (mim) 2 Cl 2 Is recycled and reused
Washing the filtrate with diethyl ether for 5 times, distilling off the solvent under vacuum, and vacuum drying to obtain C 2 (mim) 2 Cl 2 And can be reused for 2 times without loss of activity.
Example 5
Under the protection of nitrogen, compound 2 (4.5g, 25mmol) and methyl iodide (4.2g, 30mmol) were added to acetone (100 mL), and the mixture was stirred at 45 to 50 ℃ for 4 hours and then cooled to room temperature. Suction filtration and vacuum drying gave compound 3 (7.9 g, 97.8% yield) with an HPLC purity of 98.17%.
Example 6
Under the protection of argon, compound 2 (4.5g, 25mmol) and methyl iodide (5.7g, 40mmol) were added to ethyl acetate (100 mL), and after stirring and reacting at 50-55 ℃ for 4 hours, the mixture was cooled to room temperature. Suction filtration and vacuum drying gave compound 3 (7.8 g, 96.7% yield) with an HPLC purity of 98.03%.
Example 7
Compound 2 (4.5g, 25mmol) and methyl iodide (7.1g, 50mmol) were added to tetrahydrofuran (100 mL) under an argon atmosphere, and the mixture was stirred at 50 to 55 ℃ for 4 hours and then cooled to room temperature. Suction filtration and vacuum drying gave compound 3 (7.9 g, 98.1% yield) with an HPLC purity of 97.80%.
Example 8
Compound 2 (4.5g, 25mmol) and methyl iodide (10.6g, 75mmol) were added to tetrahydrofuran (100 mL) under an argon atmosphere, reacted with stirring at 55 to 60 ℃ for 4 hours, and then cooled to room temperature. The solvent was distilled off under vacuum and dried under vacuum to give compound 3 (7.6 g, yield 94.3%) with an HPLC purity of 95.63%.
Example 9
A mixture of compound 3 (6.5g, 20mmol), compound 4 (2.7g, 20mmol) and silica gel (12.5 g) was sufficiently ground with a pestle and subjected to microwave irradiation at 900W for 10 to 20 minutes. After TLC monitoring the reaction was complete, the mixture was washed by soaking in a mixture of deionized water/triethylamine, the washings were combined, the solvent was distilled off in vacuo, the residue was recrystallized from water/methanol and dried in vacuo to give compound 5 (4.2 g, yield 78.9%) with an HPLC purity of 99.53%.
Example 10
A mixture of compound 3 (6.5g, 20mmol), compound 4 (3.2g, 24mmol) and silica gel (11.7 g) was sufficiently ground with a pestle, and microwave irradiation was performed at 800W for 10 to 20 minutes. After completion of the TLC monitoring reaction, the mixture was washed by soaking in a mixture of deionized water/triethylamine, the washings were combined, the solvent was distilled off in vacuo, the residue was recrystallized from water/methanol and dried in vacuo to give compound 5 (4.3 g, yield 80.7%) with an HPLC purity of 99.35%.
Example 11
A mixture of compound 3 (6.5g, 20mmol), compound 4 (3.5g, 26mmol) and silica gel (16.3 g) was sufficiently ground with a pestle, and microwave irradiation was performed at 1000W for 10 to 20 minutes. After TLC monitoring the reaction was complete, the mixture was washed by soaking in a mixture of deionized water/triethylamine, the washings were combined, the solvent was distilled off in vacuo, the residue was recrystallized from water/methanol and dried in vacuo to give compound 5 (4.1 g, 77.5% yield) with an HPLC purity of 99.57%.
Example 12
A mixture of compound 3 (6.5g, 20mmol), compound 4 (4.1g, 30mmol) and silica gel (9.7 g) was sufficiently ground with a pestle, and microwave irradiation was performed at 700W for 10 to 20 minutes. After TLC monitoring the completion of the reaction, the mixture was washed by soaking in a mixture of deionized water and triethylamine, the washings were combined, the solvent was distilled off under vacuum, and the residue was recrystallized from water/methanol and dried under vacuum to give compound 5 (3.7 g, 70.1% yield) with an HPLC purity of 97.65%.
Example 13
Compound 5 (3.2 g, 12mmol) was added to tetrahydrofuran (20 mL), triethylamine (9 mL) was added dropwise with stirring, the reaction solution was cooled to 0 ℃ and trifluoroacetic anhydride (5 mL) was added dropwise, and after the addition was completed, the reaction solution was stirred at room temperature for 3 to 4 hours. After the completion of the reaction monitored by TLC, pH =6 to 7 was adjusted and filtered. Pulping the obtained filter cake with N, N-dimethylformamide (5 mL)/methanol (15 mL) for 1-2 hours, filtering, washing the filter cake with methanol (5 mL), and drying in vacuum to obtain a compound 6 (i.e. Topiroxostat,2.3g, yield 77.2%) with the HPLC purity of 99.77%.
Topiroxostat prepared according to the technical scheme of the invention is white crystalline powder, and a PXRD powder diffraction pattern is shown in figure 1; the purity of topiroxostat is high, the solvent residue is less, and the detection result of the finished topiroxostat product is shown in table 1.
TABLE 1
Claims (10)
1. A method for synthesizing topiroxostat is characterized by comprising the following steps:
1) Reacting the compound 1 with ammonium sulfide in an imidazole salt water solution to prepare a compound 2;
2) Under the protection of inert gas, reacting the compound 2 with methyl iodide to prepare a compound 3;
3) Reacting the compound 3, the compound 4 and silica gel under microwave irradiation to prepare a compound 5;
4) Reacting the compound 5 with trifluoroacetic anhydride to prepare topiroxostat;
2. the synthesis method according to claim 1, wherein the molar ratio of the compound 1 to the ammonium sulfide in the step 1) is 1.1 to 1.4.
3. The method of claim 1, wherein the imidazolium salt of step 1) is selected from the group consisting of C 6 (mim) 2 Cl 2 、C 4 (mim) 2 Cl 2、 C 8 (mim) 2 Cl 2 One kind of (1).
4. The synthesis method according to claim 1, wherein the molar ratio of the compound 1 to the imidazolium salt in step 1) is 1.
5. The synthesis method according to claim 1, wherein the reaction temperature in step 1) is 65-75 ℃.
6. The synthesis process according to claim 1, wherein the molar ratio of compound 2 to methyl iodide in step 2) is 1.
7. The synthesis method according to claim 1, wherein the solvent used in step 2) is one or more selected from acetone, ethyl acetate and tetrahydrofuran.
8. The synthesis method according to claim 1, wherein the reaction temperature in step 2) is 40-55 ℃.
9. The method according to claim 1, wherein the molar ratio of the compound 3 to the compound 4 in the step 3) is 1.
10. The synthesis method according to claim 1, wherein the mass ratio of the compound 3 to the silica gel in the step 3) is 1.8 to 2.5.
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