CN103724329B - Preparation method of 4-[5-(pyridyl-4-yl)-1H-[1,2,4]triazolyl-3-yl]pyridyl-2-formonitrile - Google Patents
Preparation method of 4-[5-(pyridyl-4-yl)-1H-[1,2,4]triazolyl-3-yl]pyridyl-2-formonitrile Download PDFInfo
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Abstract
The invention provides a preparation method of 4-[5-(pyridyl-4-yl)-1H-[1,2,4]triazolyl-3-yl]pyridyl-2-formonitrile, which comprises the following steps: synthesizing a compound disclosed as Formula (V) from a compound disclosed as Formula (VI) as an initial raw material, synthesizing a compound disclosed as Formula (IV), synthesizing a compound disclosed as Formula (III), and finally synthesizing a compound disclosed as Formula (I) from the compound disclosed as Formula (III) and a compound disclosed as Formula (II). The method avoids using extremely toxic substances, has the advantages of high safety, environmental protection, short reaction time, mild reaction conditions, low product cost and high purity, and is simple to operate and suitable for industrial production. The reaction formula is disclosed in the specification.
Description
Technical field
The present invention relates to the preparation method of 4-[5-(pyridin-4-yl)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN.
Background technology
4-[5-(pyridin-4-yl)-1
h-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN is a kind of non-purines xanthine oxidoreductase enzyme selectivity inhibitor, is used for the treatment of gout, hyperuricemia.In June, 2012, medicine Co., Ltd. of Fuji and three and chemistry institute jointly submit application for quotation to Japanese MHLW, on June 28th, 2013, Topiroxostat sheet gets the Green Light.
4-[5-(pyridin-4-yl)-1
h-[1,2,4] triazole-3-base] chemical structure of pyridine-2-formonitrile HCN (Topiroxostat) is as follows:
This compound open synthetic route reported mainly contains following several:
Chinese patent ZL02819276.1, EP1471065B1 report its synthetic route the earliest:
This route is first by γ-picolinic acid oxynitride (VIII) and 1-ethoxy carbonyl-2-oxyethyl group-1; 2-dihydroquinoline is reacted 1 hour under argon shield; add methyl alcohol again and react 17 hours; column chromatography purification obtains iso methyl nicotinate oxynitride (VII); again with third level natural division under argon shield back flow reaction 16 hours; column chromatography obtains formula (IV) compound, then is obtained by reacting formula (III) compound with hydrazine hydrate, then with formula (II) compound Reactive Synthesis target product (I).This route reaction time is long, the bad purifying of product, and uses costliness, highly toxic substance third level natural division, and operational danger is high, and not environmentally.
Document (Tetrahedron Letters; Vol. 49; Nb. 28; (2008); P. 4369 – 4371) report following two kinds of synthetic routes:
Route one:
This route operation steps is more, especially first performs protection step, and by past protection step, and use severe toxicity, expensive third level natural division, operational danger is high, and cost is higher.
Route two:
This route will use cheap cyanidization agent zinc cyanide, and belong to highly toxic substance, in operation, danger is very high, and environmental pollution is serious.
Summary of the invention
In order to solve the above-mentioned technical problem that prior art exists, the invention provides a kind of new 4-[5-(pyridin-4-yl)-1
h-[1,2,4] triazole-3-base] preparation method of pyridine-2-formonitrile HCN.The method avoids using highly toxic substance, safety and environmental protection, simple to operate, the reaction times is short, reaction conditions is gentle, product cost is low, purity is high, is applicable to suitability for industrialized production.
Technical scheme of the present invention is as follows:
Method of the present invention comprises the steps: that with compound formula (VI) Suo Shi be starting raw material synthesis formula V compound, resynthesis formula (IV) compound, then synthesis type (III) compound, formula (III) compound and formula (II) compound last synthesis type (I) compound, reaction formula is as follows:
。
be preferably:
Method of the present invention comprises the steps:
Step one: formula (VI) compound iso methyl nicotinate and methane amide or carboxamide mixture are obtained by reacting formula (V) compound 2-methane amide iso methyl nicotinate in the environment of sulfuric acid, ferrous sulfate (i.e. iron vitriol) and hydrogen peroxide,
Step 2: formula (V) compound 2-methane amide iso methyl nicotinate obtains formula (IV) compound 2-cyano group iso methyl nicotinate through high-efficiency dehydration agent dehydration reaction,
Step 3: formula (IV) compound 2-cyano group iso methyl nicotinate and hydrazine hydrate are obtained by reacting formula (III) compound 2-cyano group vazadrine,
Step 4: formula (III) compound 2-cyano group vazadrine and formula (II) compound react to obtain formula (I) compound 4-[5-(pyridin-4-yl)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN.
be more preferably:
Method of the present invention comprises the steps:
Step one: with compound formula (VI) Suo Shi for starting raw material, synthesis formula V compound
Formula (VI) compound iso methyl nicotinate is added in methane amide or carboxamide mixture, be cooled to-20 ~ 20 DEG C, add the vitriol oil, ferrous sulfate and hydrogen peroxide, after adding, 10 ~ 100 DEG C of reaction 2-10 hour, add sodium citrate aqueous solution, adjust pH=7 ~ 8 with sodium bicarbonate in system, with dichloromethane extraction, from product, collect formula V compound.
Step 2: formula V compound obtains formula (IV) compound through dehydration reaction
Formula V compound is joined in reaction solvent, adds dewatering agent ,-20 ~ 200 DEG C, react 0.5 ~ 6 hour, after having reacted, in system, add saturated aqueous sodium carbonate, adjust pH=7 ~ 8, separate out solid, obtain formula (IV) compound.
Step 3: formula (IV) compound is obtained by reacting formula (III) compound again with hydrazine hydrate
Be added in methyl alcohol by formula (IV) compound, add hydrazine hydrate, 0 ~ 20 DEG C is reacted 50 minutes ~ 2 hours, filters, obtains formula (III) compound.
Step 4: formula (III) compound and 4-cyanopyridine react to obtain formula (I) compound
Formula (II) compound dissolution, in alcoholic solvent, is added sodium methylate, formula (III) compound, 60 ~ 110 DEG C are reacted 2 ~ 30 hours, have reacted rear cool to room temperature, filter, obtain formula (I) compound.
In above-mentioned steps one, raw materials used mol ratio is: methane amide: formula (VI) compound=1 ~ 40:1, preferred methane amide: formula (VI) compound=30 ~ 40:1.Raw materials used when being carboxamide mixture, the mol ratio of the methane amide in carboxamide mixture and formula (VI) compound is 1 ~ 40:1, preferably 30 ~ 40:1.
In above-mentioned steps one, the mol ratio of other raw materials is: ferrous sulfate: hydrogen peroxide: iso methyl nicotinate=1 ~ 2:1 ~ 2:1.
In above-mentioned steps one, reaction solvent carboxamide mixture refers to mixture a kind of in methane amide and methylene dichloride, chloroform, tetracol phenixin, methyl-sulphoxide, 1,2-ethylene dichloride, acetonitrile or acetone.
In above-mentioned steps one, the temperature adding ferrous sulfate and hydrogen peroxide is-20 ~ 20 DEG C, after adding, and temperature of reaction is 10 ~ 100 DEG C, and the reaction times is 2 ~ 10 hours; The temperature preferably adding ferrous sulfate and hydrogen peroxide is 0 ~ 10 DEG C, after adding, and temperature of reaction is 10 ~ 30 DEG C, and the reaction times is 3 hours.
In above-mentioned steps two, reaction solvent used is: methane amide, N, one in dinethylformamide, N,N-dimethylacetamide, methylene dichloride, chloroform, tetracol phenixin, acetonitrile, ethyl acetate, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, toluene, benzene, sherwood oil or alkane.
In above-mentioned steps two, dewatering agent used be cyanuric chloride, trifluoroacetic anhydride, aceticanhydride, phosphorus oxychloride, sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, polyphosphoric acid, Vanadium Pentoxide in FLAKES, the vitriol oil, N, N'-dicyclohexylcarbodiimide (DCC),
two (trimethyl silicon based) trifluoroacetamideor the one in 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU).
In above-mentioned steps two, temperature of reaction is-20 ~ 200 DEG C, and the reaction times is 0.5 ~ 6 hour; Being preferably temperature of reaction is 10 ~ 30 DEG C, and the reaction times is 1 ~ 2 hour.
In above-mentioned steps three, temperature of reaction is 0 ~ 20 DEG C, and the reaction times is 50 minutes ~ 2 hours; Preferable reaction temperature is 15 ~ 20 DEG C, and the reaction times is 50 minutes.
In above-mentioned steps four, described alcoholic solvent is one in methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol etc. or any two kinds of mixing, and temperature of reaction is 60 ~ 110 DEG C, and the reaction times is 2 ~ 30 hours.
The advantage of the present invention preparation method required for protection:
(1) preparation method of the present invention, the time often walking reaction is shorter, operation and aftertreatment simple;
(2) preparation method of the present invention, avoid using highly toxic substance, reaction conditions is gentle, and reaction environment is good, safety and environmental protection;
(3) preparation method of the present invention, with cheap tube-nursery, greatly reduce cost, purity is high, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but not as a limitation of the invention.
Embodiment 1: the preparation method 1 of formula V compound
226 g (1.65 mol) formula (VI) compound is added to 2 L(59.2mol) in methane amide, be cooled to 0-10 DEG C, add 90 ml (1.65 mol) vitriol oil, keep 0-10 DEG C, 690 g (2.48 mol) iron vitriol and 278 ml (2.26 mol) 30% hydrogen peroxide is alternately added in system, system blackening, after adding, be raised to room temperature reaction 3 hours, stopped reaction, the 7 L sodium citrate aqueous solutions of 800g (2.74 mol) are added in system, then pH=7-8 is adjusted with sodium bicarbonate, three extractions are divided with 6 L methylene dichloride, organic layer is washed by saturated salt again, concentrating under reduced pressure, obtain about 130 g solids, with 800 ml sherwood oil making beating, dry, obtain 115 g off-white color solids and formula V compound, yield: 38.7%.
1HNMR (600MHz, DMSO-
d6), ppm: 8.86(1H, d, N=CH), 8.430(1H, s, NC=CH), 8.27(H, brs, NH
2), 7.84(2H, brs, NH
2), 8.03(1H, d, N=CHCH), 3.94(3H, s, CH
3)。
Embodiment 2: the preparation method 2 of formula V compound
226 g (1.65 mol) formula (VI) compound is added to 2 L(59.2mol) in methane amide, be cooled to-20 DEG C, add 90 ml (1.65 mol) vitriol oil, remain on less than 20 DEG C, 690 g (2.48 mol) iron vitriol and 278 ml (2.26 mol) 30% hydrogen peroxide is alternately added in system, system blackening, after adding, be heated to 100 DEG C of reactions 2 hours, stopped reaction, the 7 L sodium citrate aqueous solutions of 800 g (2.74 mol) are added in system, then pH=7-8 is adjusted with sodium bicarbonate, three extractions are divided with 6 L methylene dichloride, organic layer is washed by saturated salt again, concentrating under reduced pressure, obtain about 130 g solids, with 800 ml sherwood oil making beating, dry, obtain 100 g off-white color solids and formula V compound, yield: 33.6%.
Embodiment 3: the preparation method 3 of formula V compound
226 g (1.65 mol) formula (VI) compound is added to 2 L(59.2mol) in methane amide, be cooled to-20 DEG C, add 90 ml (1.65 mol) vitriol oil, keep less than 10 DEG C, 690 g (2.48 mol) iron vitriol and 278 ml (2.26 mol) 30% hydrogen peroxide is alternately added in system, system blackening, after adding, 10 DEG C are kept to react 10 hours, stopped reaction, the 7 L sodium citrate aqueous solutions of 800 g (2.74 mol) are added in system, then pH=7-8 is adjusted with sodium bicarbonate, three extractions are divided with 6 L methylene dichloride, organic layer is washed by saturated salt again, concentrating under reduced pressure, obtain about 130 g solids, with 800 ml sherwood oil making beating, dry, obtain 118 g off-white color solids and formula V compound, yield: 39.7%.
Embodiment 4: the preparation method 4 of formula V compound
226 g (1.65 mol) formula (VI) compound is added to 56ml (1.65 mol) methane amide and 300 ml methyl-sulphoxides, be cooled to-20 DEG C, add 90 ml (1.65 mol) vitriol oil, keep temperature not higher than 20 DEG C, 459 g (1.65 mol) iron vitriol and 203 ml (1.65 mol) 30% hydrogen peroxide is alternately added in system, system blackening, after adding, be heated to 100 DEG C of reactions 2 hours, stopped reaction, the 7 L sodium citrate aqueous solutions of 800 g (2.74 mol) are added in system, then pH=7-8 is adjusted with sodium bicarbonate, three extractions are divided with 6 L methylene dichloride, organic layer is washed by saturated salt again, concentrating under reduced pressure, obtain about 105 g solids, with 800 ml sherwood oil making beating, dry, obtain 95 g off-white color solids and formula V compound, yield: 31.9%.
Embodiment 5: the preparation method 5 of formula V compound
226 g (1.65 mol) formula (VI) compound is added to 1680ml (49.5 mol) methane amide and 300ml methyl-sulphoxide, be cooled to-20 DEG C, add 90 ml (1.65 mol) vitriol oil, keep temperature not higher than 20 DEG C, 459 g (1.65 mol) iron vitriol and 203 ml (1.65 mol) 30% hydrogen peroxide is alternately added in system, system blackening, after adding, be heated to 100 DEG C of reactions 2 hours, stopped reaction, the 7 L sodium citrate aqueous solutions of 800 g (2.74 mol) are added in system, then pH=7-8 is adjusted with sodium bicarbonate, three extractions are divided with 6 L methylene dichloride, organic layer is washed by saturated salt again, concentrating under reduced pressure, obtain about 115 g solids, with 800 ml sherwood oil making beating, dry, obtain 100 g off-white color solids and formula V compound, yield: 33.6%.
Embodiment 6: the preparation method 6 of formula V compound
226 g (1.65 mol) formula (VI) compound is added to the mixed solution of 2240 ml (66 mol) methane amide and 200ml acetone, be cooled to-20 DEG C, add 90 ml (1.65 mol) vitriol oil, keep less than 10 DEG C, 556 g (3.3 mol) iron vitriol and 246 ml (3.3 mol) 30% hydrogen peroxide is alternately added in system, system blackening, after adding, 10 DEG C are kept to react 10 hours, stopped reaction, the 7 L sodium citrate aqueous solutions of 800 g (2.74 mol) are added in system, then pH=7-8 is adjusted with sodium bicarbonate, three extractions are divided with 6 L methylene dichloride, organic layer is washed by saturated salt again, concentrating under reduced pressure, obtain about 126 g solids, with 800 ml sherwood oil making beating, dry, obtain 123 g off-white color solids and formula V compound, yield: 36.6%.
Embodiment 7: the preparation method 1 of formula (IV) compound
90 g (0.5 mol) formula V compound is joined 450 ml DMF(N, dinethylformamide) in, add 54 g (0.3 mol) cyanuric chloride, room temperature reaction 1 hour, after having reacted, in system, add 120 ml saturated aqueous sodium carbonates, adjust pH=7-8, separate out solid, add 900 ml frozen water, filter, then wash with water and sherwood oil, 50 DEG C of dry 71 g solids and formula (IV) compounds, yield: 87.7%.
1HNMR (600MHz, DMSO-
d6), ppm: 8.98(1H, t, N=CH), 8.42(1H, s, NC=CH), 8.16(1H, q, N=CHCH), 3.94(3H, s, CH
3)。
Embodiment 8: the preparation method 2 of formula (IV) compound
90 g (0.5 mol) formula V compound is joined in 900 ml tetrahydrofuran (THF)s, is cooled to-25 DEG C, add 100 g triethylamines, add 210 g(1 mol again) trifluoroacetic anhydride ,-20 DEG C are reacted 6 hours, after having reacted, saturated aqueous sodium carbonate is added in system, adjust pH=7-8, separate out solid, add 900 ml frozen water, filter, wash with water and sherwood oil again, 50 DEG C of dry 62 g solids and formula (IV) compounds, yield: 76.57%.
Embodiment 9: the preparation method 3 of formula (IV) compound
90 g (0.5 mol) formula V compound is joined in 900 ml tetrahydrofuran (THF)s, is cooled to-15 DEG C, add 100 g triethylamines, add 210 g(1 mol again) trifluoroacetic anhydride, 0 DEG C is reacted 2 hours, after having reacted, saturated aqueous sodium carbonate is added in system, adjust pH=7-8, separate out solid, add 900 ml frozen water, filter, wash with water and sherwood oil again, 50 DEG C of dry 60 g solids and formula (IV) compounds, yield: 74.1%.
Embodiment 10: the preparation method 4 of formula (IV) compound
9 g (0.05 mol) formula V compound is added in 18 ml phosphorus oxychloride, 106 DEG C of back flow reaction 2 hours, after having reacted, remove phosphorus oxychloride under reduced pressure, saturated aqueous sodium carbonate is added in system, adjust pH=7-8, separate out solid, add 500 ml frozen water, filter, wash with water and sherwood oil again, 50 DEG C of dry 5.5 g solids and formula (IV) compounds, yield: 67.9%.
Embodiment 11: the preparation method 5 of formula (IV) compound
9 g (0.05 mol) formula V compound is added in the 18 ml vitriol oils, 200 DEG C are reacted 0.5 hour, after having reacted, pour in frozen water, saturated aqueous sodium carbonate is added in system, adjust pH=7-8, separate out solid, add 500 ml frozen water, filter, wash with water and sherwood oil again, 50 DEG C of dry 5 g solids and formula (IV) compounds, yield: 61.7%.
Embodiment 12: the preparation method 6 of formula (IV) compound
9 g (0.05 mol) formula V compound is added in 30 ml methylene dichloride, add 7.6 g DBU(1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene) (0.05 mol), be cooled to 0 DEG C, keep 0 ~ 5 DEG C, drip 8.1 g(0.05 mol) dichloro etherophosphoric acid, room temperature reaction 2 hours, after having reacted, saturated aqueous sodium carbonate is added in system, adjust pH=7-8, with 100 ml extraction into ethyl acetate, with anhydrous magnesium sulfate drying, filter, remove solvent under reduced pressure, obtain solid to wash with sherwood oil again, 50 DEG C of dry 5.8 g solids and formula (IV) compounds, yield: 71.6%.
Embodiment 13: the preparation method 1 of formula (III) compound
By 40 g(0.25 mol) formula (IV) compound is added in 400 ml methyl alcohol, be cooled to 15 ~ 20 DEG C, add 40 g(0.65 mol) hydrazine hydrate, after adding, keep 15 ~ 20 DEG C to react 50 min, filter, with 20 ml ice methanol wash column, wash with 40 ml sherwood oils, drying obtains 20 g off-white color solids and formula (III) compound, yield: 50% again.
1HNMR(600MHz,DMSO-
d6), ppm:10.28(1H, brs, NH), 8.90(1H, d, N=CHCH), 8.32(1H, s, NC=CH), 8.05(1H, q, NH
2), 4.74(2H, brs, NH
2)。
Embodiment 14: the preparation method 2 of formula (III) compound
By 40 g(0.25 mol) formula (IV) compound is added in 400 ml methyl alcohol, be cooled to-5 DEG C, add 40 g(0.65 mol) hydrazine hydrate, after adding, keep 0 DEG C to react 2 hours, filter, with 20 ml ice methanol wash column, wash with 40 ml sherwood oils, drying obtains 18 g off-white color solids and formula (III) compound, yield: 45% again.
Embodiment 15: the preparation method 1 of formula (I) compound
By 11.55 g(0.11 mol) formula (II) compound dissolution is in 200 ml methyl alcohol, add 1.2 g(0.022 mol) sodium methylate, room temperature reaction 50 min, then 18 g(0.11 mol are added) formula (III) compound, heat 60-65 DEG C of reaction 1 hour, 200 ml propyl carbinols are added while normal pressure steams methyl alcohol again, 100-105 DEG C is reacted 2 hours, react rear cool to room temperature, filter, 20 ml methyl alcohol and 40 ml petroleum ether filter cakes, drying obtains 19 g yellow product and formula (I) compound, yield: 69.1%.
1HNMR(600MHz,DMSO-
d6),ppm:15.42(1H, brs, NH), 8.92(1H, s, N=CH), 8.80(2H, s, N=CH), 8.53(1H, s, N=CCH), 8.30(1H, d, -C=CH), 8.01(2H, d, -C=CH)。
Embodiment 16: the preparation method 2 of formula (I) compound
By 11.55 g(0.11 mol) formula (II) compound dissolution is in 200 ml methyl alcohol, add 1.2 g(0.022 mol) sodium methylate, room temperature reaction 50 min, then 18 g(0.11 mol are added) formula (III) compound, heats 60-65 DEG C of reaction 30 hours, has reacted rear cool to room temperature, filter, 20 ml methyl alcohol and 40 ml petroleum ether filter cakes, drying obtains 18 g yellow product and formula (I) compound, yield: 65.4%.
Embodiment 17: the preparation method 3 of formula (I) compound
By 11.55 g(0.11 mol) formula (II) compound dissolution is in 200 ml propyl carbinols, add 1.2 g(0.022 mol) sodium methylate, room temperature reaction 50 min, then 18 g(0.11 mol are added) formula (III) compound, heats 100-105 DEG C of reaction 2 hours, has reacted rear cool to room temperature, filter, 20 ml methyl alcohol and 40 ml petroleum ether filter cakes, drying obtains 17 g yellow product and formula (I) compound, yield: 61.8%.
Claims (5)
1. compound 4-[5-(pyridine-4-base)-1 shown in formula (I)
h-[1,2,4] triazole-3-base] preparation method of pyridine-2-formonitrile HCN, it is characterized in that, comprise the steps: that with compound formula (VI) Suo Shi be starting raw material synthesis formula V compound, resynthesis formula (IV) compound, then synthesis type (III) compound, formula (III) compound and formula (II) compound last synthesis type (I) compound, reaction formula is as follows:
。
2. according to the preparation method described in claim 1, it is characterized in that, described step comprises:
Step one: formula (VI) compound and methane amide or carboxamide mixture are obtained by reacting formula (V) compound in the environment of sulfuric acid, ferrous sulfate and hydrogen peroxide;
Step 2: formula (V) compound obtains formula (IV) compound through high-efficiency dehydration agent dehydration reaction, described high-efficiency dehydration agent is selected from cyanuric chloride, trifluoroacetic anhydride, aceticanhydride, phosphorus oxychloride, sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, polyphosphoric acid, Vanadium Pentoxide in FLAKES, the vitriol oil, N, N'-dicyclohexylcarbodiimide (DCC), two (trimethyl silicon based) trifluoroacetamide or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene;
Step 3: formula (IV) compound and hydrazine hydrate are obtained by reacting formula (III) compound;
Step 4: formula (III) compound and formula (II) compound react to obtain formula I compound.
3. according to the preparation method described in claim 2, it is characterized in that, described step comprises:
Step one: formula (VI) compound iso methyl nicotinate is added in methane amide or carboxamide mixture, be cooled to-20 ~ 20 DEG C, add the vitriol oil, ferrous sulfate and hydrogen peroxide, after adding, 10 ~ 100 DEG C of reaction 2-10 hour, add sodium citrate aqueous solution, adjust pH=7 ~ 8 with sodium bicarbonate in system, with dichloromethane extraction, from product, collect formula V compound;
Step 2: join in reaction solvent by formula V compound, adds high-efficiency dehydration agent, and-20 ~ 200 DEG C are reacted 0.5 ~ 6 hour, after having reacted, in system, add saturated aqueous sodium carbonate, adjust pH=7 ~ 8, separate out solid, obtain formula (IV) compound;
Step 3: formula (IV) compound is added in methyl alcohol, adds hydrazine hydrate, 0 ~ 20 DEG C is reacted 50 minutes ~ 2 hours, filters, obtains formula (III) compound;
Step 4: formula (II) compound dissolution, in alcoholic solvent, is added sodium methylate, formula (III) compound, 60 ~ 110 DEG C are reacted 2 ~ 30 hours, have reacted rear cool to room temperature, filter, obtain formula (I) compound.
4. according to the preparation method described in claim 3, it is characterized in that, mol ratio raw materials used in step one is: methane amide: formula (VI) compound=1 ~ 40:1, ferrous sulfate: hydrogen peroxide: formula (VI) compound=1 ~ 2:1 ~ 2:1, reaction solvent carboxamide mixture refers to the mixture of methane amide and methylene dichloride, chloroform, tetracol phenixin, methyl-sulphoxide, 1,2-ethylene dichloride, acetonitrile or acetone;
In step 2, reaction solvent used is selected from methane amide, N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, methylene dichloride, chloroform, tetracol phenixin, acetonitrile, ethyl acetate, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, toluene, benzene, sherwood oil or alkane;
Alcoholic solvent described in step 4 is one in methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or any two kinds of mixing.
5. according to the preparation method described in claim 4, it is characterized in that, mol ratio raw materials used in step one is: methane amide: formula (VI) compound=30 ~ 40:1, and the temperature adding ferrous sulfate and hydrogen peroxide is 0 ~ 10 DEG C, temperature of reaction is 10 ~ 30 DEG C, and the reaction times is 3 hours;
The temperature of reaction of step 2 is 10 ~ 30 DEG C, and the reaction times is 1 ~ 2 hour;
The temperature of reaction of step 3 is 15 ~ 20 DEG C, and the reaction times is 50 minutes.
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| CN105693699B (en) * | 2015-03-30 | 2019-06-18 | 苏州晶云药物科技股份有限公司 | Hold in the palm his crystal form and preparation method thereof of pyrrole department |
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| CN105130958B (en) * | 2015-08-31 | 2017-10-31 | 济南康和医药科技有限公司 | The preparation technology of 5 (pyridine radicals of 2 cyano group 4) 3 (4 pyridine radicals) 1,2,4 triazoles |
| CN105294656A (en) * | 2015-10-10 | 2016-02-03 | 大道隆达（北京）医药科技发展有限公司 | Preparation process and method for topiroxostat |
| CN106336399A (en) * | 2015-11-03 | 2017-01-18 | 江苏悦兴药业有限公司 | Preparation method of Topiroxostat process impurity |
| CN107573330B (en) * | 2017-09-30 | 2020-11-10 | 河北中医学院 | Preparation method of topiroxostat |
| CN107652271B (en) * | 2017-11-06 | 2020-06-16 | 上海中拓医药科技有限公司 | Preparation method of topiroxostat crystal form I |
| CN110776501B (en) * | 2019-08-22 | 2021-04-02 | 联宁（苏州）生物制药有限公司 | Preparation method of drug toxin PNU-159682 for antibody drug conjugate and intermediate thereof |
| CN112645931A (en) * | 2020-12-16 | 2021-04-13 | 山东罗欣药业集团股份有限公司 | Preparation method of medicine for treating chronic hyperuricemia |
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