Background technology
Gout a kind ofly causes the common disease of uricogenesis exception because of purine metabolic disturbance, and united state is classified as one of 21 century 20 large chronic disease, is the second largest metabolism class disease being only second to diabetes." hyperuricemia and gout treatment China Consensus of experts " is pointed out, hyperuricemia (hyperuricemia, HUA) popular totally presents the trend raised year by year, the male sex is higher than women, and have certain regional disparity, south and coastal economy developed regions other regional morbiditys domestic compared with the same period high, the more important thing is, the patient groups of HUA presents the trend of more and more rejuvenation.According to statistics, the eighties in 20th century, American-European countries HUA morbidity was 2% ~ 18%.Within 1998, Shanghai HUA morbidity is 10.1%; Within 2003, Nanjing HUA morbidity is 13.3%; Within 2004, Guangzhou HUA morbidity is up to 21.8%; Within 2009, Shandong HUA morbidity is 16.7%, within 2004, obviously increases, and increase with age than with area.
While HUA height is popular, large quantifier elimination evidence has highlighted the harm of HUA.HUA and metabolism syndrome (me tabolic syndrome, MS), diabetes B (type 2 diabetes mellitus, T2DM), hypertension, cardiovascular disorder, chronic nephropathy, gout etc. are closely related, are the independent hazard factors of these disease developments.
The gout caused for hyperuricemia and hyperuricemia at present, carries out corresponding living environment adjustment and various pharmacological agent according to period (premonition phase) of premonition gout outbreak, gout stage of attack and gout catabasis respectively.That is, prevent with regard to adjusting everyday environments and being aided with colchicine during the premonition phase, just treat centered by the pharmacological agenies such as steroid class and nonsteroidal anti-inflammatory agent are during stage of attack, outbreak just instructs patient to improve living habit after alleviating, clearly after the low mo(u)ld bottom half of uric acid excretion or uric acid produce hyperfunction type when improveing incomplete, give and probenecid, what BBR was such has uric acid excretion effect, what sulfinpyrazone was such has suppression uric acid resorption, the improvement aciduria effect that Citrate trianion is such, the medicine like this that xanthine oxidase inhibitor Zyloric etc. has suppression uric acid generation effect is treated.If just taken colchicine at premorbid 2-3 hour, so it just can suppress chemotaxis and the phagolysis of neutrophilic granulocyte etc., thus can prevent the morbidity of 90%.But this medicine has multiple side effect, will control at bottom line, judged that period of disease carries out taking also very difficult when using.
Although based on pharmacological agent, can be used for the medicine that uric acid produces hyperfunction type and but only have Zyloric, and its meta-bolites alloxanthine is likely to accumulate in body and forms calculus.And it was further reported that this medicine can cause the side effects such as eruption, poor kidney, hepatitis.
Holder takes charge of him, English Topiroxostat by name, and commodity are called TOPILORIC, chemistry is by name: 4-[5-(pyridin-4-yl)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN is a kind of non-purines xanthine oxidoreductase enzyme selectivity inhibitor.On June 28th, 2013, holder his sheet of department obtains the approval listing of Japanese MHLW, and be used for the treatment of gout, hyperuricemia, the structure of a holder Si Tashi (1) compound is as follows:
This compound open synthetic route reported mainly contains following several:
1. the synthetic route reported the earliest of Chinese patent ZL02819276.1, EP1471065B1:
This route is first by γ-picolinic acid oxynitride and 1-ethoxy carbonyl-2-oxyethyl group-1; 2-dihydroquinoline is reacted 1 hour under argon shield; add methyl alcohol reaction again; column chromatography purification obtains iso methyl nicotinate oxynitride; again with trimethylammonium cyano group pasc reaction; column chromatography obtains the cyanalation product of formula, is obtained by reacting vazadrine compounds with hydrazine hydrate, then with 4-cyanopyridine 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.
2. document (Tetrahedron Letters; Vol.49; Nb.28; (2008); P.4369-4371) synthetic route reported:
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.
3. document (Tetrahedron Letters; Vol.49; Nb.28; (2008); P.4369-4371) another synthetic route reported:
This route steps is simple, although the cyanidization agent zinc cyanide used is comparatively cheap, and large usage quantity, and the yield of cyanation step only has 66%, 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 holder his preparation method of department of improvement.
The present invention adopts following technical scheme:
Preparation method of the present invention comprises the steps:
With formula (6) compound vazadrine for starting raw material, react production (4) triazole compounds with formula (5) compound 4-cyanopyridine N-oxide compound, formula (4) triazole compounds is at copper catalyst (CuX) and zinc cyanide (Zn (CN)
2) and dimethylaminoethyl chloride exist under, production (3) cyanalation triazole compounds, formula (3) compound is under tosic acid exists, production (2) compound, finally alkalize with mineral alkali and obtain target formula (1) compound of the present invention, namely holder takes charge of him, and reaction formula is as follows:
wherein, X is I or Br.
The discovery that contriver is surprised, as copper catalyst (CuX), when especially the copper catalyst of monovalence exists, can improve the activity of the cyanating reagents such as zinc cyanide greatly, and make the temperature of reaction gentleer, yield improves greatly.
Preferably, preparation method of the present invention comprises the steps:
Step one: with formula (6) compound vazadrine for starting raw material, with formula (5) compound 4-cyanopyridine N-oxide compound in methanol solvate, sodium methoxide catalyzed lower production (4) triazole compounds;
Step 2: formula (4) triazole compounds is at copper catalyst (CuX) and zinc cyanide (Zn (CN)
2) and under dimethylaminoethyl chloride exists, take acetonitrile as solvent, production (3) cyanalation triazole compounds, described copper catalyst is one or both in cuprous bromide or cuprous iodide;
Step 3: formula (3) compound, under tosic acid monohydrate exists, sloughs protecting group production (2) compound, solvent used is one or more in ethyl acetate, Virahol or acetone;
Step 4: formula (2) compound mineral alkali exist under, obtain formula (1) compound, mineral alkali used is one or more in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, calcium carbonate, sodium hydroxide.
Wherein: the reaction times of step 2 is 3-12 hour, and temperature of reaction is 50-120 DEG C, formula (4) compound used: dimethylaminoethyl chloride: zinc cyanide: the mol ratio of copper catalyst is: 1: 2.0 ~ 3.0: 1.0 ~ 1.5: 0.01 ~ 0.2; Preferably, the reaction times of step 2 is 5-9 hour, and temperature of reaction is 80-90 DEG C, formula (4) compound used: dimethylaminoethyl chloride: zinc cyanide: the mol ratio of copper catalyst is: 1: 2.0 ~ 2.5: 1.0 ~ 1.2: 0.05 ~ 0.15; Most preferred formula (4) compound: dimethylaminoethyl chloride: zinc cyanide: the mol ratio of copper catalyst is: 1: 2.2: 1.2: 0.1.
Preferably, the copper catalyst of step 2 described above is cuprous iodide.
Wherein: formula (3) compound that step 3 is used: the mol ratio of tosic acid monohydrate is: 1.0: 2.5 ~ 3.0.
Wherein: step 4 mineral alkali used is preferably sodium bicarbonate or sodium carbonate, most preferably sodium bicarbonate.
Beneficial effect of the present invention:
(1) preparation method of the present invention, the time often walking reaction is shorter, operation and aftertreatment simple;
(2) use of copper catalyst, greatly reduces the consumption of zinc cyanide, makes reaction conditions gentleer;
(3) product purity that obtains of preparation method of the present invention is high, is applicable to suitability for industrialized production.
Embodiment
Embodiment 1: the preparation of formula (4) compound 4-(5-(pyridin-4-yl)-1H-1,2,4-triazole-3-base) pyridine-N-oxide
1.20g (0.01mol) 4-cyanopyridine-N-oxide compound (formula 5 compound) is dissolved in 50ml methyl alcohol, then adds sodium methylate 50mg, be stirred to dissolving.Then vazadrine (formula 6 compound) 1.37g (0.01mol) is added, reflux 10 hours.After reaction terminates, the solid of precipitation is leached, with dry with vacuum pump after washed with methanol, obtain product as yellow powder and formula (4) compound 1.87g, yield 78%.
Embodiment 2: the preparation of formula (4) compound 4-(5-(pyridin-4-yl)-1H-1,2,4-triazole-3-base) pyridine-N-oxide
12.0g (0.10mol) 4-cyanopyridine-N-oxide compound (formula 5 compound) is dissolved in 500ml methyl alcohol, then adds sodium methylate 1.0g, be stirred to dissolving.Then vazadrine (formula 6 compound) 13.7g (0.10mol) is added, reflux 15 hours.After reaction terminates, the solid of precipitation is leached, with dry with vacuum pump after washed with methanol, obtain product as yellow powder and formula (4) compound 18.2g, yield 77%.
Embodiment 3: the preparation of formula (3) compound 3-(2-cyanopyridine-4-base)-N, N-dimethyl-5-(pyridin-4-yl)-1H-1,2,4-triazole-1-methane amide.
By formula (4) compound 2.39g (10mmol), dimethylaminoethyl chloride (0.22ml, 22mmol), zinc cyanide (1.40g, 12mmol), cuprous iodide 0.19g (1mmol) is dissolved in 100ml acetonitrile, mixture reacts 5 hours at 80 DEG C, TLC detection reaction (n-hexane/ethyl acetate=1: 1), after completion of the reaction, be cooled to room temperature, add 100ml water stirring reaction 5-30 minute, discard organic layer, aqueous layer with ethyl acetate extracts three times, each 100ml, merge organic layer, anhydrous sodium sulfate drying, decompression steams solvent, obtain crude product, crude product n-hexane/ethyl acetate=4: 1 column chromatographies, obtain faint yellow solid 2.97g, yield 93%, HPLC purity (normalization method): 97.7%, fusing point: 112-113 DEG C, 1H NMR (500 MHz, CDCl3): 63.16 (3H, s), 3.29 (3H, s), 8.10-8.00 (3H, m), 8.23 (1H, m), 8.79 (2H, d, J=5.0Hz), 8.91 (1H, d, J=5.0Hz).
Embodiment 4: the preparation of formula (3) compound 3-(2-cyanopyridine-4-base)-N, N-dimethyl-5-(pyridin-4-yl)-1H-1,2,4-triazole-1-methane amide.
By formula (4) compound 23.9g (0.10mol), dimethylaminoethyl chloride (2.2ml, 0.22mol), zinc cyanide (12.87g, 0.11mol), cuprous iodide 2.1g (11mmol) is dissolved in 500ml acetonitrile, mixture reacts 5 hours at 90 DEG C, TLC detection reaction (n-hexane/ethyl acetate=1: 1), after completion of the reaction, be cooled to room temperature, add 300ml water stirring reaction 5-30 minute, discard organic layer, aqueous layer with ethyl acetate extracts three times, each 300ml, merge organic layer, anhydrous sodium sulfate drying, decompression steams solvent, obtain crude product 27.8g, yield 87%, HPLC purity (normalization method): 90.7%, next step can be directly used in.
Embodiment 5: the preparation of formula (3) compound 3-(2-cyanopyridine-4-base)-N, N-dimethyl-5-(pyridin-4-yl)-1H-1,2,4-triazole-1-methane amide.
By formula (4) compound 23.9g (0.10mol), dimethylaminoethyl chloride (2.2ml, 0.22mol), zinc cyanide (11.7g, 0.10mol), cuprous iodide 0.95g (5mmol) is dissolved in 500ml acetonitrile, mixture reacts 6 hours under reflux state, TLC detection reaction (n-hexane/ethyl acetate=1: 1), after completion of the reaction, be cooled to room temperature, add 300ml water stirring reaction 5-30 minute, discard organic layer, aqueous layer with ethyl acetate extracts three times, each 300ml, merge organic layer, anhydrous sodium sulfate drying, decompression steams solvent, obtain crude product 27.1g, yield 85%, HPLC purity (normalization method): 91.2%, next step can be directly used in.
Embodiment 6: the preparation of formula (3) compound 3-(2-cyanopyridine-4-base)-N, N-dimethyl-5-(pyridin-4-yl)-1H-1,2,4-triazole-1-methane amide.
By formula (4) compound 2.39g (10mmol), dimethylaminoethyl chloride (0.22ml, 22mmol), zinc cyanide (1.40g, 12mmol), cuprous bromide 0.19g (1mmol) is dissolved in 100ml acetonitrile, mixture reacts 5 hours at 85 DEG C, TLC detection reaction (n-hexane/ethyl acetate=1: 1), after completion of the reaction, be cooled to room temperature, add 100ml water stirring reaction 5-30 minute, discard organic layer, aqueous layer with ethyl acetate extracts three times, each 100ml, merge organic layer, anhydrous sodium sulfate drying, decompression steams solvent, obtain crude product, crude product n-hexane/ethyl acetate=4: 1 column chromatographies, obtain faint yellow solid 2.85g, yield 89%, HPLC purity (normalization method): 96.8%.
Embodiment 7: the preparation of formula (3) compound 3-(2-cyanopyridine-4-base)-N, N-dimethyl-5-(pyridin-4-yl)-1H-1,2,4-triazole-1-methane amide.
By formula (4) compound 23.9g (0.10mol), dimethylaminoethyl chloride (2.2ml, 0.22mol), zinc cyanide (14.0g, 0.12mol), cuprous iodide 1.0g (5.5mmol) is dissolved in 500ml acetonitrile, mixture reacts 9 hours under reflux state, TLC detection reaction (n-hexane/ethyl acetate=1: 1), after completion of the reaction, be cooled to room temperature, add 300ml water stirring reaction 5-30 minute, discard organic layer, aqueous layer with ethyl acetate extracts three times, each 300ml, merge organic layer, anhydrous sodium sulfate drying, decompression steams solvent, obtain crude product 26.8g, yield 84%.
Embodiment 8: the preparation of formula (2) compound 4-[5-(pyridin-4-yl)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN tosilate
By formula (3) compound 3.19g (10mmol), tosic acid monohydrate 4.75g (25mmol) is dissolved in 50ml Virahol, mixture at 80 DEG C, stirring reaction 7 hours, TLC detection reaction, after completion of the reaction, steam solvent, residuum ethyl acetate washs 3 times, each 10ml, drying obtains off-white color solid 4.19g, yield 100%, fusing point 236.5-237.4 DEG C.
Embodiment 9: the preparation of formula (2) compound 4-[5-(pyridin-4-yl)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN tosilate
By formula (3) compound 31.9g (0.10mol), tosic acid monohydrate 5.7g (0.30mol) is dissolved in 500ml acetone, mixture was in reflux state stirring reaction 8 hours, TLC detection reaction, after completion of the reaction, steams solvent, residuum ethyl acetate washs 3 times, each 10ml, drying obtains off-white color solid 41.8g, yield 99%.
Embodiment 10: the preparation of formula (1) compound 4-[5-(pyridin-4-yl)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN
Formula (2) compound 4.2g (10mmol) is added 10ml ethanol and 10ml water, and stirring at room temperature is dissolved.Add again sodium hydrogen carbonate solution (sodium bicarbonate 0.84g add water 10ml formed solution), stirring at room temperature 2 hours, filtration obtains crystal, then water, washing with alcohol is used, vacuum-drying, obtains pale yellow crystals target compound and formula (1) compound 2.39g, yield 95%, HPLC purity (normalization method): 99.5%, single assorted < 0.1%.
Be 3.6%, through the patient that compound sulfur lotion is cured, pay a return visit after 1 month, all recur.