CN110698395B - Preparation method of topiroxostat intermediate - Google Patents
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- CN110698395B CN110698395B CN201911004466.8A CN201911004466A CN110698395B CN 110698395 B CN110698395 B CN 110698395B CN 201911004466 A CN201911004466 A CN 201911004466A CN 110698395 B CN110698395 B CN 110698395B
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- 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
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Abstract
The invention discloses a preparation method of a topiroxostat intermediate, wherein the intermediate is 2-cyanoisoniazide, and the method comprises the step of carrying out substitution reaction on 2-cyanoisoniazide R ester and hydrazine acid salt under the action of alkali to generate the topiroxostat intermediate 2-cyanoisoniazide. The method provided by the invention has the beneficial effects of convenient operation, cheap and easily available raw materials and high yield and purity.
Description
Technical Field
The invention relates to a preparation method of a topiroxostat intermediate.
Background
Topiroxostat (Topiroxostat) is a non-purine selective xanthine oxidoreductase inhibitor developed by Fuji chemical Co., Ltd, Japan, and the third and chemical research institute, and can selectively and reversibly inhibit xanthine oxidoreductase and reduce serum uric acid level. Approved by japanese PMDA for marketing in 2013, month 8. Can be used for treating gout and hyperuricemia.
Chemical name of topiroxostat: (5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2, 4-triazole) having the following structural formula:
topiroxostat (Topiroxostat)
The preparation of topiroxostat intermediate 2-cyanoisoniazid from 2-cyanoisoniazid and hydrazine hydrate is reported in documents CN201710939134.3, Chinese Journal of Pharmaceuticals 2016, 47(7), and the like. The route in patent CN201710939134.3 has the defects of complicated post-treatment, high energy consumption, low yield of 76.5-85%, easy occurrence of side reaction as follows to generate a byproduct III, and subsequent influence on the purity and yield of topiroxostat; the route of Chinese Journal of Pharmaceuticals 2016, 47(7) suffers from the disadvantages of large amounts of hydrazine hydrate and low yields. Therefore, a preparation method of the topiroxostat intermediate 2-cyano isoniazid (I) with convenient operation, low energy consumption and high yield is found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the preparation method of the topiroxostat intermediate 2-cyanoisoniazide (I), which has the advantages of convenient operation, low energy consumption, high yield and high purity.
The technical scheme of the invention is as follows:
the intermediate is 2-cyano isoniazid, the structural formula of which is shown as a formula (I), and the intermediate is characterized by comprising the following steps:
1) dissolving 2-cyanoisonicotinic acid R ester shown as a formula (II) in a reaction solvent A, adding hydrazine acid salt at one time at the temperature of minus 10-50 ℃, stirring for 1-10 hours, dropwise adding alkali at the temperature of minus 10-30 ℃, preserving heat and reacting for 2-10 hours, after the reaction is finished, performing suction filtration, pulping a filter cake by using a solvent B, performing suction filtration, and drying to obtain the 2-cyanoisonicotinic acid hydrazine shown as a formula (I).
The preparation method of the topiroxostat intermediate is characterized in that in the step 1), the 2-cyanoisonicotinic acid R ester (II) is any one or more of 2-cyanoisonicotinic acid methyl ester, 2-cyanoisonicotinic acid ethyl ester, 2-cyanoisonicotinic acid isopropyl ester and 2-cyanoisonicotinic acid butyl ester.
The preparation method of the topiroxostat intermediate is characterized in that the reaction solvent A in the step 1) is any one or more of methanol, ethanol, isopropanol, tert-amyl alcohol, butanol, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide, and the volume of the organic solvent A is 2-30 times, preferably 3-10 times, of the mass of the 2-cyanoisonicotinic acid R ester.
The preparation method of the topiroxostat intermediate is characterized in that the hydrazine hydrochloride in the step 1) is selected from any one or more of hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine monohydrobromide, hydrazine sulfate, hydrazine acetate and tert-butyl hydrazine hydrochloride.
The preparation method of the topiroxostat intermediate is characterized in that the alkali in the step 1) is selected from any one or more of ammonia water, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, pyridine, triethylamine, tri-N-propylamine, tri-N-pentylamine and N, N-diisopropylethylamine.
The preparation method of the topiroxostat intermediate is characterized in that the molar ratio of the 2-cyanoisonicotinic acid R ester to the hydrazine acid salt to the alkali in the step 1) is 1: (1-3): (1-4).
The preparation method of the topiroxostat intermediate is characterized in that the pulping solvent B in the step 1) is selected from any one or more of methanol, ethanol, isopropanol, tert-amyl alcohol, butanol, tetrahydrofuran and water, and the volume of the pulping solvent B is 2-10 times, preferably 2-7 times, of the mass of the 2-cyano isonicotinic acid R ester.
The preparation method of the topiroxostat intermediate is characterized in that the reaction temperature in the step 1) is-10-30 ℃, and the reaction time is 2-10 hours.
The reaction route of the invention is as follows:
the invention provides a preparation method of topiroxostat intermediate 2-cyano isoniazid, which aims to solve the problems of more byproducts and low yield.
Drawings
FIG. 1 is a 1H NMR spectrum of Compound (I).
FIGS. 2-1, 2-2 and 2-3 are LC-MS spectra of the compound (I).
FIG. 3 is a 1H NMR spectrum of compound (III).
FIG. 4-1 and FIG. 4-2 are LC-MS spectra of compound (III).
Detailed description of the preferred embodiment
The following examples are helpful in understanding the present invention, but are not intended to limit the scope of the present invention.
Example 1:
adding 150mL of ethanol and 2-cyanoisonicotinic acid methyl ester (30.0 g and 0.19 mol) into a 250mL three-neck flask, adding hydrazine monohydrochloride (12.67 g and 0.19 mol) at 0 ℃ at one time, stirring at 0 ℃ for 2.5 hours, dropwise adding 150.0mL of water at 0 ℃, dropwise adding 3% sodium hydroxide solution, adjusting the pH value to 7-8, stirring at the constant temperature for 2 hours, carrying out vacuum filtration, pulping with 60.0mL of ethanol, carrying out vacuum filtration, and drying in a vacuum drying oven at 45 ℃ to obtain 28.4g of 2-cyanoisonicotinic hydrazine (I), yellow solid, yield: 94.6%, HPLC: 97.1 percent.
Example 2:
adding 150mL of ethanol and 2-cyanoisonicotinic acid methyl ester (30.0 g and 0.19 mol) into a 250mL three-neck flask, adding hydrazine monohydrochloride (14.4 g and 0.21 mol) at 0 ℃, stirring for 2.5 hours at 0 ℃, transferring into an ice-water bath, controlling the temperature to be 0-5 ℃, dropwise adding 3% sodium hydroxide solution, adjusting the pH value to be 7-8, stirring for 2 hours at the constant temperature, performing vacuum filtration, pulping with 60.0mL of ethanol, performing vacuum filtration, and drying in a vacuum drying oven at 45 ℃ to obtain 28.9g of 2-cyanoisonicotinic hydrazine (I), wherein the yield is as follows: 96.3%, HPLC: 98.6 percent.
Example 3:
adding 150mL of LDMF and methyl 2-cyanoisonicotinate (30.0 g and 0.17 mol) into a 250mL three-neck flask, stirring at room temperature, adding hydrazine monohydrochloride (14.4 g and 0.21 mol) at 0 ℃ at one time, stirring at 0 ℃ for 2.5 hours, adding 150.0mL of water dropwise at 0 ℃, adding 3% sodium hydroxide solution dropwise, adjusting the pH value to 7-8, stirring at constant temperature for 2 hours, performing vacuum filtration, pulping with 60.0mL of ethanol, performing vacuum filtration, drying in a 45 ℃ vacuum drying box, and drying in a 45 ℃ vacuum drying box to obtain 26.7g of 2-cyanoisonicotinate hydrazine (I), wherein the yield is as follows: 90.0%, HPLC: 99.2 percent.
Example 4:
adding 130mL of methanol and ethyl 2-cyanoisonicotinate (30.0 g and 0.17 mol) into a 250mL three-neck flask, stirring at room temperature, adding hydrazine monohydrochloride (13.0 g and 0.19 mol) at room temperature at one time, stirring at 25 ℃ for 3 hours, transferring into an ice-water bath, controlling the temperature to be 0-5 ℃, dropwise adding 150.0mL of water, dropwise adding 3% potassium hydroxide solution, controlling the temperature to be 0-5 ℃, controlling the pH value to be 7-8, stirring at a constant temperature for 3 hours, carrying out reduced pressure suction filtration, pulping with 60.0mL of water, carrying out reduced pressure suction filtration, and drying in a vacuum drying oven at 45 ℃ to obtain 26.7g of 2-cyanoisonicotinate (I), a yellow solid, and the yield: 97.0%, HPLC: 99.2 percent.
Example 5:
adding 90mL of LDMF and 2-cyano ethyl isonicotinate (30.0 g and 0.17 mol) into a 250mL three-neck flask, adding hydrazine monohydrochloride (12.3 g and 0.18 mol) at 0 ℃, stirring for 2 hours at 0 ℃, controlling the temperature to be 5-10 ℃, dropwise adding triethylamine, dropwise adding 150.0mL of methanol, controlling the temperature to be 5-10 ℃, controlling the pH value to be 7-8, stirring for 3 hours at the constant temperature, performing vacuum filtration, pulping with 55.0mL of water, performing vacuum filtration, and drying in a 45 ℃ vacuum drying oven to obtain 27.3g of 2-cyano ethyl isonicotinate (I), wherein the yield is as follows: 91.1%, HPLC: 99.0 percent.
Experimental example 6:
adding 150mL of tetrahydrofuran and 2-cyanoisonicotinic acid propyl ester (30.0 g and 0.16 mol) into a 250mL three-neck flask, stirring at room temperature, adding hydrazine monohydrobromide (17.8 g and 0.17 mol) at one time at room temperature, stirring at 25 ℃ for 4 hours, controlling the temperature to be 0-5 ℃, dropwise adding n-propylamine, dropwise adding 150.0mL of water, controlling the temperature to be 0-5 ℃, controlling the pH value to be 7-8, stirring at constant temperature for 5 hours, performing vacuum filtration, pulping with 70.0mL of tetrahydrofuran, performing vacuum filtration, and drying in a vacuum drying oven at 45 ℃ to obtain 25.6g of 2-cyanoisonicotinic acid hydrazine (I), yellow solid, yield: 92.7%, HPLC: 98.5 percent.
Experimental example 7:
adding 100mL of methanol and 2-cyanoisonicotinic acid ethyl ester (30.0 g and 0.17 mol) into a 250mL three-neck flask, stirring at room temperature, adding hydrazine sulfate (23.8 g and 0.18 mol) at room temperature at one time, stirring at 25 ℃ for 1 hour, controlling the temperature to be 5-10 ℃, dropwise adding N, N-diisopropylethylamine, dropwise adding 150.0mL of water, controlling the temperature to be 5-10 ℃ and the pH value to be 7-8, stirring at a constant temperature for 4 hours, performing vacuum filtration, pulping with 80.0mL of water, performing vacuum filtration, and drying in a vacuum drying oven at 45 ℃ to obtain 25.7g of 2-cyanoisonicotinic hydrazine (I), yellow solid, yield: 93.4%, HPLC: 98.8 percent.
Experimental example 8:
24.6g, yellow solid, yield: 89.4%, HPLC: 93.1 percent.
Adding 130mL of isopropanol and ethyl 2-cyanoisonicotinate (30.0 g and 0.17 mol) into a 250mL three-neck flask, adding hydrazine acetate (23.9 g and 0.26 mol) at 25 ℃, stirring at the constant temperature for 7 hours, controlling the temperature to be 5-10 ℃, dropwise adding a 3% sodium carbonate solution, adjusting the pH to be 7-8, stirring at the constant temperature for 9 hours, performing vacuum filtration, pulping with 75.0mL of water, performing vacuum filtration, and drying in a vacuum drying oven at 45 ℃ to obtain 2-cyanoisonicotinate (I)
Experimental example 9:
adding 100mL of tert-amyl alcohol and 2-cyano isonicotinic acid propyl ester (30.0 g and 0.16 mol) into a 250mL three-neck flask, adding hydrazine monohydrobromide (27.1 g and 0.24 mmol) at 15 ℃, stirring at a constant temperature for 3 hours, controlling the temperature to be 0-5 ℃, dropwise adding triethylamine, controlling the pH value to be 7-8, dropwise adding 120mL of water, stirring at a constant temperature for 7 hours, carrying out vacuum filtration, pulping with 80.0mL of water, carrying out vacuum filtration, and drying in a vacuum drying oven at 45 ℃ to obtain 24.6g of 2-cyano isonicotinic acid hydrazine (I), namely yellow solid, yield: 95.7%, HPLC: 98.5 percent.
Comparative example 1
150mL of ethanol and methyl 2-cyanoisonicotinate (30.0 g, 0.19 mol) are added into a 250mL three-neck flask, 9.5g of hydrazine hydrate (12.67 g, 0.19 mol) is dropwise added at-15 ℃, 30 minutes of reaction is completed, the mixture is stirred at-15 ℃ for 2.5 hours, TLC monitors the reaction end point, the reaction is stopped, 150.0mL of water is dropwise added at-10 ℃, stirring is carried out at the constant temperature for 2 hours, reduced pressure suction filtration is carried out, 60.0mL of ethanol water is used for beating, reduced pressure suction filtration is carried out, and drying is carried out in a vacuum drying oven at 45 ℃ to obtain 21.6g of 2-cyanoisonicotinate (I), yellow solid and yield: 72.0%, HPLC: 93.5 percent.
Comparative example 2
Adding 150mL of ethanol and 2-cyanoisonicotinic acid methyl ester (30.0 g and 0.19 mol) into a 250mL three-neck flask, adding hydrazine monohydrochloride (14.4 g and 0.21 mol) at 60 ℃, stirring for 2.5 hours at 60 ℃, dropwise adding 150.0mL of water at 0 ℃, dropwise adding 3% sodium hydroxide solution, adjusting the pH value to 7-8, stirring for 2 hours under heat preservation, carrying out vacuum filtration, pulping with 60.0mL of ethanol, and carrying out vacuum filtration to obtain 20.4g of 2-cyanoisonicotinyl hydrazine (I), namely yellow solid, yield: 68.0%, HPLC: 89.7 percent.
Comparative example 3
Adding 150mL of ethanol and 2-cyanoisonicotinic acid methyl ester (30.0 g and 0.19 mol) into a 250mL three-neck flask, adding hydrazine monohydrochloride (39.1 g and 0.57 mol) at 0 ℃, stirring at 0 ℃ for 2.5 hours, dripping 150.0mL of water at 0 ℃, dripping 3% sodium hydroxide solution, adjusting the pH value to 7-8, keeping the temperature and stirring for 2 hours, carrying out vacuum filtration, pulping with 60.0mL of ethanol, and carrying out vacuum filtration to obtain 14.3g of 2-cyanoisonicotinyl hydrazine (I), yellow solid, yield: 47.7%, HPLC: 74.9 percent.
The reaction products obtained in experimental example 1, experimental example 2, experimental example 3, comparative example 1, comparative example 2 and comparative example 3 were analyzed, and the results are shown in table 1:
TABLE 1
Profile characterization of compound (I):
1H NMR (600 MHz, DMSO) δ (ppm): 4.72(2H, s), 8.05(1H, dd), 8.31(1H, dd), 8.88(1H, dd), 10.27(1H,brs).
MS: m/z [M+H]+: 163.2.
profile characterization of compound (iii):
1H NMR (400 MHz, DMSO) : δ(ppm) :4.62 (2H, brs),5.43 (2H, brs), 5.78 (2H, s), 7.62-7.64(1H,dd), 8.28(1H, s),8.58-8.59(1H,d),10.13(1H,s).
MS: m/z [M+H ]+: 195.3.
Claims (1)
1. a preparation method of a topiroxostat intermediate is disclosed, wherein the intermediate is 2-cyanoisoniazid, the structural formula of which is shown in a formula (I), and the preparation method is characterized by comprising the following steps:
dissolving 2-cyanoisonicotinic acid R ester shown as a formula (II) in a reaction solvent A, adding hydrazine monohydrochloride at one time at 0 ℃, stirring for 2.5 hours, dropping sodium hydroxide at the temperature of 0-5 ℃, carrying out heat preservation reaction for 2-10 hours, carrying out suction filtration after the reaction is finished, pulping a filter cake with a solvent B, carrying out suction filtration, and drying to obtain 2-cyanoisonicotinic acid hydrazine shown as a formula (I);
wherein, the R ester of 2-cyanoisonicotinic acid is methyl ester of 2-cyanoisonicotinic acid; the solvent A and the solvent B are both selected from ethanol; the molar ratio of the added 2-cyanoisonicotinic acid R ester to hydrazine monohydrochloride is 1: 1.
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Citations (4)
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| CN101910168A (en) * | 2007-10-25 | 2010-12-08 | 埃克塞利希斯股份有限公司 | Tropane compounds |
| CN104803879A (en) * | 2015-03-27 | 2015-07-29 | 江苏长青农化南通有限公司 | Preparation technology of methoxyfenozide |
| CN106699596A (en) * | 2016-12-30 | 2017-05-24 | 江苏永安化工有限公司 | Preparation process of methoxyfenozide |
| CN107652271A (en) * | 2017-11-06 | 2018-02-02 | 上海中拓医药科技有限公司 | A kind of Topiroxostat crystal formation I preparation method |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101910168A (en) * | 2007-10-25 | 2010-12-08 | 埃克塞利希斯股份有限公司 | Tropane compounds |
| CN104803879A (en) * | 2015-03-27 | 2015-07-29 | 江苏长青农化南通有限公司 | Preparation technology of methoxyfenozide |
| CN106699596A (en) * | 2016-12-30 | 2017-05-24 | 江苏永安化工有限公司 | Preparation process of methoxyfenozide |
| CN107652271A (en) * | 2017-11-06 | 2018-02-02 | 上海中拓医药科技有限公司 | A kind of Topiroxostat crystal formation I preparation method |
Non-Patent Citations (2)
| Title |
|---|
| Convergent synthesis and cytotoxicity of novel trifluoromethyl-substituted (1H-pyrazol-1-yl)(quinolin-4-yl) methanones;Helio G. Bonacorso，等;《Journal of Fluorine Chemistry》;20160826;31-40 * |
| Discovery of 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051-a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia;Takahiro Sato，等;《Bioorganic & Medicinal Chemistry Letters》;20090902;第16卷;6225–6229 * |
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