CN108047148A - A kind of preparation method of the western Nader's impurity of thunder - Google Patents
A kind of preparation method of the western Nader's impurity of thunder Download PDFInfo
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- CN108047148A CN108047148A CN201711460923.5A CN201711460923A CN108047148A CN 108047148 A CN108047148 A CN 108047148A CN 201711460923 A CN201711460923 A CN 201711460923A CN 108047148 A CN108047148 A CN 108047148A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N30/14—Preparation by elimination of some components
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, it is related to a kind of preparation method of the western Nader's impurity of thunder.Preparation method of the present invention, step are as follows:Step 1, with 5 bromine 4 (4 cyclopropyl naphthalene, 1 base) 1,2,4 triazoles of 4H, 3 mercaptan for starting material and 2, substitution reaction occurs for 2 dibromoacetic acid methyl esters (esters such as ethyl ester);Step 2, the aqueous solution of products therefrom and lithium hydroxide generation hydrolysis obtains 2 bromine 2 ((5 bromine 4 (4 cyclopropyl naphthalene, 1 base) 1,2,4 triazoles of 4H, 3 base) is thio) acetic acid.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of preparation method of the western Nader's impurity of thunder
Background technology
The western Nader of thunder (lesinurad), the entitled 2- of chemistry [[the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- tri-
Azoles -3- bases] sulfenyl] acetic acid, ground by AstraZeneca (AstraZeneca) original, respectively in December, 2015 the U.S., 2016 years 2
Month listed in European Union, trade name Zurampic, be 1 inhibitor of urate transporter of first listing, it is clinical mainly and xanthine
Oxidase inhibitor (such as Allopurinol, Febustat) is combined, and for treating the relevant hyperuricemia of gout, has higher peace
Quan Xing, good market prospect.
The western Nader's structural formula of thunder is as follows:
It is mainly prepared by following reaction scheme, first using 4- cyclopropyl -1- naphthalenylisothiocyanates as starting material
First with formyl hydrazine reaction, then cyclization is formed in the western Nader's key of thunder in DMF (dimethylformamide) solution of sodium acid carbonate
Mesosome 5- amino -4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan are finally substituted, bromo, hydrolysis obtains
The western Nader of thunder (1), synthetic route is as follows:
For the western Nader of thunder as bulk pharmaceutical chemicals, the control of wherein impurity is the western Nader's quality critical place of thunder, therefore studies thunder west
The impurity synthesis of Nader is of great significance.
Present inventors studied the western Nader's synthesis technology of a variety of thunders, wherein issuable impurity includes:
2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulphonyl) methyl acetate (2);
2- ((4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulphonyl) methyl acetate (3);
2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulphonyl) acetic acid (4);
The bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- sulfonic acid (5);
The bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan (6);
Bis- bromo- 2- of 2,2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) is thio) acetic acid (7)
2- ((4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) are thio) acetic acid (8);
2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) sulfinyl) acetic acid (9);
The bromo- 2- of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) are thio) acetic acid (10) etc..
Wherein impurity (10) has no document report, and present inventors studied impurity (10) and impurity (7) to find, impurity (10)
All it is the by-product of bromo-reaction with impurity (7), the two structure is similar, it is difficult to separation and purifying.
For this purpose, the present invention provides a kind of from thunder western Nader's bulk pharmaceutical chemicals point to obtain the superior in quality western Nader's bulk pharmaceutical chemicals of thunder
Separate out the method for impurity (10), while a kind of preparation method of impurity (10) be provided, to by the use of gained impurity (10) as pair
The quality of the western Nader's bulk pharmaceutical chemicals of thunder is detected and controlled according to product.
The content of the invention
In the prior art, do not report impurity (10) in the related synthesis document of the western Nader of thunder, do not refer to impurity (10) yet
Source, preparation process, minimizing technology and analyzing detecting method.
The present invention is based on the preparation of the western Nader of thunder, impurity (10) present in the western Nader's preparation process of thunder contain in order to control
Amount improves the product quality of the western Nader's bulk pharmaceutical chemicals of thunder, and the present invention provides a kind of synthetic method of the western Nader's impurity (10) of thunder, institutes
Obtaining impurity (10) can use as the impurity reference substance of the western Nader's bulk pharmaceutical chemicals quality control of thunder.Further offer of the invention
A kind of method of quality control of western Nader's bulk pharmaceutical chemicals of thunder and the detection method of impurity (10).
Analysis method the present invention also provides the western Nader's impurity (10) of thunder and the removal side in the western Nader's bulk pharmaceutical chemicals of thunder
Method, so as to improve the purity of the western Nader's bulk pharmaceutical chemicals of thunder.
For this purpose, the present invention provides a kind of western bromo- 2- of Nader's impurity 2- of thunder ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-
1,2,4- triazole -3- bases) thio) preparation method of acetic acid (impurity (10)), this method can be directed to synthesize the impurity, and purity is very
It is high.
The method of the present invention, synthetic route are as follows:
For achieving the above object, the present invention adopts the following technical scheme that:The technique is miscellaneous with the technique of the western Nader of thunder
Matter (6) is starting material, and the chemical entitled bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan are substituted,
Hydrolysis obtains the western Nader's impurity (10) of thunder.
The preparation method of the present invention, step are as follows:
Step 1, with the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan are starting material and 2,
Substitution reaction occurs for 2- dibromoacetic acids methyl esters (esters such as ethyl ester);
Step 2, the aqueous solution of products therefrom and lithium hydroxide generation hydrolysis obtains the bromo- 2- of 2- ((5- bromo- 4- (4- rings
Propyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) thio) acetic acid.
Wherein, in the substitution reaction of step 1,2,2- dibromoacetic acid methyl esters (esters such as ethyl ester) and 5- bromo- 4- (4- cyclopropyl
Naphthalene -1- bases) -4H-1, the molar ratio of 2,4- triazole -3- mercaptan is 1~3:1, in substitution reaction, use potassium carbonate or sodium carbonate for
Acid binding agent, using DMF as solvent.
Wherein, in the substitution reaction of step 1, the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan
Substitution reaction occurs with 2,2- dibromoacetic acids methyl esters or 2,2- ethyl dibromoacetate first, after the completion of reaction, water, which is added dropwise, makes product
It is precipitated, product is through washing, ethyl acetate washing, finally dry solid.
Wherein, in the hydrolysis of step 2, lithium hydroxide and the bromo- 2- of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -
4H-1,2,4- triazole -3- bases) thio) methyl acetate or the bromo- 2- of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4-
Triazole -3- bases) thio) molar ratio of ethyl acetate is 1~5:1.
Wherein, in the hydrolysis of step 2, using tetrahydrofuran as solvent, the aqueous solution of lithium hydroxide, which is added dropwise, makes reaction complete
Into, then plus hydrobromic acid aqueous solution tune PH=6~7 between, organic solvent is then removed under reduced pressure, water is mutually with hydrobromic acid aqueous solution tune
Between PH=2~3, ethyl acetate extraction, organic phase and then washing, drying, evaporated under reduced pressure obtain crude product, and crude product is washed through ethyl acetate
It washs, is drying to obtain.
It is obtained according to the technique that is conventionally synthesized of the western Nader of thunder in the western Nader's crude product of thunder, typically contains a small amount of impurity (10), I
Develop a kind of method of quality control of the western Nader's bulk pharmaceutical chemicals of thunder and the high-efficiency liquid chromatography method for detecting of impurity (10), to miscellaneous
Matter (10) good separating effect, specific method are as follows:
It is that filler (recommends Ultimate, XB-C18,250 × 4.6mm, 5 μ with octadecylsilane chemically bonded silica
m);Mobile phase A is phosphate buffer, and Mobile phase B is methanol, is eluted by with Gradient;Detection wavelength is 225nm, stream
Speed is 1.0ml per minute, and column temperature is 30 DEG C.
It is each appropriate according to product that precision weighs impurity (10), solubilizer [methanol-water (50:50)] dissolve and dilute and every 1ml is made
In mixed solution containing about WB004 0.2mg and each 2 μ g of impurity, as system suitability solution.Precision measures system suitability
10 μ l of solution inject liquid chromatograph, record chromatogram, and the peak-to-peak separating degree of each ingredient should be not less than 1.5, and theoretical cam curve is pressed
WB004 peaks meter must not be less than 2000.
Measuring method takes this product appropriate, adds appropriate solvent [methanol-water (50:50)] dissolve and quantify dilution and be made in every 1ml
Solution containing about 0.2mg, as test solution;Precision measures test solution 1ml and puts in 50ml measuring bottles, and solubilizer is diluted to
Scale shakes up, and precision measures 1ml and puts in 20ml measuring bottles, and solubilizer is diluted to scale, shakes up, as contrast solution.Precision measures
Test solution and each 10 μ l of contrast solution, are injected separately into liquid chromatograph, record chromatogram, API appearance relative retention times
About 16 minutes, impurity (10) appearance relative retention time about 20.5 minutes.
It is obtained according to the technique that is conventionally synthesized of the western Nader of thunder in the western Nader's crude product of thunder, typically contains a small amount of impurity (10), I
Go out the purification process of impurity (10) by experimental development, this method is easy to operate, good impurity removing effect, and specific method is as follows:
Take the western Nader's crude product of the thunder containing impurity (10), add in the 10-15 times of ethyl acetate measured, be heated to reflux 1-2 it is small when,
Then it is down to room temperature filtering product, dry highly finished product.
Beneficial effects of the present invention
First, which is controlled syntheses, with the process contaminants (6) of the western Nader of thunder for starting material, the three of the compound
5 have connected bromine atoms on azoles ring, and the bromo-reaction that the later and NBS (N- bromo-succinimides) evaded occurs avoids
The generation of impurity (7) has obtained the higher product of purity.
Secondly, the present invention provides a kind of method of quality control of western Nader's bulk pharmaceutical chemicals of thunder and the detection method of impurity (10),
The minimizing technology of impurity (10) in a kind of western Nader's bulk pharmaceutical chemicals of thunder is provided simultaneously, so as to improve the pure of the western Nader's bulk pharmaceutical chemicals of thunder
Degree.
Meanwhile the technique starting material is easy to get, reaction condition is mild, and post processing is relatively easy, substantially without side reaction, receives
Rate is higher.
Description of the drawings
Fig. 1:The western Nader's crude product liquid phase test map of thunder
Fig. 2:The western Nader's highly finished product liquid phase test map of thunder
Specific embodiment
With reference to the embodiment of the present invention, the present invention will be further described.It is necessarily pointed out that following embodiment
It is served only for the further instruction of the present invention, it is impossible to be interpreted as limiting the scope of the invention, which is skilled in technique
Personnel can make the present invention according to foregoing invention content some nonessential modifications and adaptations.
Embodiment 1:The preparation process of the western Nader's impurity (10) of thunder
Step 1:The bromo- 2- of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) are thio) acetic acid
The preparation of methyl esters
DMF265ml, the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan are added in 1L reaction bulbs
48g, stirring and dissolving.Temperature control adds in potassium carbonate 30g stirring 15min at 10~15 DEG C, and temperature control is added dropwise 2,2 at 10~15 DEG C ,-dibromo
Methyl acetate 58g, add rear system be warmed to room temperature that the reaction was continued naturally 4~5 it is small when.Purified water is added dropwise at 5~10 DEG C in temperature control
530ml, add continue stirring 1 it is small when, filter solid, filter cake with purified water 100ml elute, solid add in ethyl acetate 160ml,
Temperature control stirs 30min at 25~30 DEG C and filters solid, and 40~45 DEG C of vacuum drying 8~12 obtain the bromo- 2- of 2- ((the bromo- 4- of 5- when small
(4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) thio) methyl acetate 60g, yield:87.0%, ESI-MS (m/
z):498.0[M+H]+;1HNMR(400MHz,DMSO-d6):8.60 (d, J=8.3Hz, 1H), 7.75 (m, 1H), 7.63~
7.70 (m, 2H), 7.47 (m, 1H), 7.15 (d, J=8.2Hz, 1H), 5.31 (S, 1H), 3.67 (S, 3H), 1.50 (m, 1H),
1.11~1.20 (m, 2H), 0.84~0.95 (m, 2H).
Step 2:The bromo- 2- of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) are thio) acetic acid
(10) preparation
Add in THF250ml in 1L reaction bulbs, the bromo- 2- of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- tri-
Azoles -3- bases) thio) methyl acetate 60g cooling stirrings.Water (250ml) solution of lithium hydroxide (15g) is added dropwise at 0-5 DEG C for temperature control,
When insulation reaction 1 is small, it is added dropwise between hydrobromic acid aqueous solution tune PH=6~7.Then organic solvent is depressurized away, water mutually uses hydrogen bromine
Between aqueous acid tune PH=2~3, system adds in ethyl acetate 500ml stirrings 15min and separates organic layer, uses purified water successively
250ml cleans organic layer, will separate organic anhydrous sodium sulfate that is added to and dry 30min.45 DEG C are dried under reduced pressure organic phase.It will be spin-dried for
Crude product add in ethyl acetate 100ml and be stirred at room temperature 30min, filter solid, 45~50 DEG C of forced air dryings 8~12 obtain 2- when small
Bromo- 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) are thio) acetic acid (10) 50g, yield
85.7%, purity 99.5% (HPLC), ESI-MS (m/z):484.2[M+H]+;1H NMR(400MHz,DMSOd6):8.59(d,
J=8.4Hz, 1H), 7.75 (m, 1H), 7.61~7.71 (m, 2H), 7.45 (d, J=7.6Hz, 1H), 7.17 (d, J=8.1Hz,
1H), 4.83 (s, 1H), 2.83 (m, 1H), 1.08~1.41 (m, 2H), 0.86~0.99 (m, 2H).
Embodiment 2:The purifying process of the western Nader's impurity (10) of thunder
Step 1:The western Nader's crude product 10g of the thunder containing impurity (10) (purity 99.50%, 10 content 0.37% of impurity) is taken,
Add in 150ml ethyl acetate, be heated to reflux 1-2 it is small when, be then down to room temperature filtering product, 60-70 DEG C of drying 12 obtains smart when small
Product 9.1g, yield 91%, purity 99.91% (impurity (10) does not detect).Crude product and highly finished product liquid phase test map see Fig. 1 and
Fig. 2.
Claims (5)
1. a kind of preparation method of the western Nader's impurity (10) of thunder, which is characterized in that the method, step are as follows:
Step 1, with the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan are starting material and 2,2- bis-
Substitution reaction occurs for methyl bromoacetate (esters such as ethyl ester);
Step 2, the aqueous solution of products therefrom and lithium hydroxide generation hydrolysis obtains the bromo- 2- of 2- ((5- bromo- 4- (4- cyclopropyl
Naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) thio) acetic acid.
2. preparation method according to claim 1, which is characterized in that wherein, in the substitution reaction of step 1,2,2- dibromos
Methyl acetate (esters such as ethyl ester) and the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1, the molar ratio of 2,4- triazole -3- mercaptan are
1~3:1, in substitution reaction, potassium carbonate or sodium carbonate are used as acid binding agent, using DMF as solvent.
3. preparation method according to claim 1, which is characterized in that wherein, in the substitution reaction of step 1, the bromo- 4- of 5-
(4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- mercaptan first with 2,2- dibromoacetic acids methyl esters or 2,2- dibromoacetic acid second
Substitution reaction occurs for ester, and after the completion of reaction, water, which is added dropwise, is precipitated product, and product is washed through washing, ethyl acetate, finally dry
Solid.
4. preparation method according to claim 1, which is characterized in that wherein, in the hydrolysis of step 2, lithium hydroxide
With the bromo- 2- of 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) are thio) methyl acetates or the bromo- 2- of 2-
The molar ratio of ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases) are thio) ethyl acetate is 1~5:1.
5. preparation method according to claim 1, which is characterized in that wherein, in the hydrolysis of step 2, with tetrahydrochysene furan
It mutters as solvent, the aqueous solution of lithium hydroxide, which is added dropwise, completes reaction, then plus between hydrobromic acid aqueous solution tune PH=6~7, then
Organic solvent is removed under reduced pressure, mutually between hydrobromic acid aqueous solution tune PH=2~3, ethyl acetate extracts water, organic phase and then water
It washes, dry, evaporated under reduced pressure obtains crude product, and crude product is washed through ethyl acetate, is drying to obtain.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108822013A (en) * | 2018-09-17 | 2018-11-16 | 浙江乐普药业股份有限公司 | A kind of Lesinurad intermediate impurities dimer and its preparation method and application |
CN111220728A (en) * | 2020-01-19 | 2020-06-02 | 北京鑫开元医药科技有限公司海南分公司 | Detection method for effectively separating Raschindyleigh and main impurities |
CN112778223A (en) * | 2021-01-25 | 2021-05-11 | 海南鑫开源医药科技有限公司 | Preparation method of Raschindde oxidation impurities |
CN113979958A (en) * | 2021-12-14 | 2022-01-28 | 海南鑫开源医药科技有限公司 | Preparation method of Raschindde related impurities |
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WO2014008295A1 (en) * | 2012-07-03 | 2014-01-09 | Ardea Biosciences, Inc. | Manufacture of 2- (5- bromo-4 (-cyclopropylnaphthalen-1-yl) -4h-1,2,4-triazol-3-ylthio) acetic acid |
CN103524440A (en) * | 2013-10-15 | 2014-01-22 | 苏州鹏旭医药科技有限公司 | Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad |
CN105294585A (en) * | 2014-07-02 | 2016-02-03 | 成都海创药业有限公司 | Compound for treating gout |
CN106831619A (en) * | 2017-01-13 | 2017-06-13 | 中国药科大学 | The preparation method of the western Nader's impurity of thunder |
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2017
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2014008295A1 (en) * | 2012-07-03 | 2014-01-09 | Ardea Biosciences, Inc. | Manufacture of 2- (5- bromo-4 (-cyclopropylnaphthalen-1-yl) -4h-1,2,4-triazol-3-ylthio) acetic acid |
CN103524440A (en) * | 2013-10-15 | 2014-01-22 | 苏州鹏旭医药科技有限公司 | Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad |
CN105294585A (en) * | 2014-07-02 | 2016-02-03 | 成都海创药业有限公司 | Compound for treating gout |
CN106831619A (en) * | 2017-01-13 | 2017-06-13 | 中国药科大学 | The preparation method of the western Nader's impurity of thunder |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108822013A (en) * | 2018-09-17 | 2018-11-16 | 浙江乐普药业股份有限公司 | A kind of Lesinurad intermediate impurities dimer and its preparation method and application |
CN111220728A (en) * | 2020-01-19 | 2020-06-02 | 北京鑫开元医药科技有限公司海南分公司 | Detection method for effectively separating Raschindyleigh and main impurities |
CN112778223A (en) * | 2021-01-25 | 2021-05-11 | 海南鑫开源医药科技有限公司 | Preparation method of Raschindde oxidation impurities |
CN113979958A (en) * | 2021-12-14 | 2022-01-28 | 海南鑫开源医药科技有限公司 | Preparation method of Raschindde related impurities |
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