CN108822013A - A kind of Lesinurad intermediate impurities dimer and its preparation method and application - Google Patents

A kind of Lesinurad intermediate impurities dimer and its preparation method and application Download PDF

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CN108822013A
CN108822013A CN201811081736.0A CN201811081736A CN108822013A CN 108822013 A CN108822013 A CN 108822013A CN 201811081736 A CN201811081736 A CN 201811081736A CN 108822013 A CN108822013 A CN 108822013A
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dimer
lesinurad
impurity
intermediate impurities
compound
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成碟
杨成钰
颜剑波
姜小余
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Zhejiang Le Pu Pharmaceutical Ltd By Share Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
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Abstract

The present invention relates to a kind of Lesinurad intermediate impurities dimers and its preparation method and application, belong to pharmaceutical synthesis and analysis technical field.In order to solve the existing impurity that cannot effectively identify in synthesis process, a kind of Lesinurad intermediate impurities dimer and its preparation method and application is provided, the method of the dimer includes III compound of formula containing the impurity dimer for being reacted 4- cyclopropyl -1- naphthalenylisothiocyanate and formylhydrazine, and column chromatography for separation obtains corresponding dimer or reacts to obtain the impurity dimer by 4- cyclopropyl -1- naphthalenylisothiocyanate and hydrazine.The present invention is capable of providing for the analysis and monitoring to impurity in the intermediate synthesis process, effectively provides the reference substance of the impurity, is conducive to the quality requirement for improving Lesinura intermediate and product, is conducive to the yield and production efficiency that improve product；And simple process, it is easily operated.

Description

A kind of Lesinurad intermediate impurities dimer and its preparation method and application
Technical field
The present invention relates to a kind of Lesinurad intermediate impurities dimers and its preparation method and application, belong to drug conjunction At and analysis technical field.
Background technique
Gout is the crystal correlation arthropathy caused by monosodium urate mineralization, with purine metabolic disturbance and (or) uric acid Hyperuricemia caused by excretion is reduced is directly related.Global patient with gout is up to more than 2,000 ten thousand.Lesinurad is a kind of rush urine Acid excretion oral medicine, can inhibit the sub- URAT1 of renal proximal tubules uric acid transporter.Entitled 2- [[the bromo- 4- of 5- of chemistry of Lesinurad (4- cyclopropyl -1- naphthalene) -4H-1,2,4- triazole -3- bases] thio] acetic acid, No. CAS is 878672-00-5, the chemistry of the drug Structural formula is as follows：
Currently, report is extremely active about the technique of Lesinurad and the research of crystal form.If existing report is with 1- naphthalene Amine -4- cyclopropyl be starting material, after react with thiophosgene preparation 4- cyclopropyl -1- naphthalenylisothiocyanate, then with formylhydrazine Reaction, then, cyclization obtains key intermediate 4- (4- cyclopropyl -1- base) -4H-1,2,4- triazole -3- under sodium carbonate effect Mercaptan, using be condensed with methyl bromoacetate, NBS bromo, hydrolysis, obtain corresponding Lesinurad product.The reaction can lead to Cross following equation expression：
Meanwhile what is be related to is also more, still, synthesizes about it is reported for the impurity in Lesinurad synthesis process The report of the impurity structure and its control that generate in journey is seldom, brings many difficulties to the quality studied and control Lesinurad. For inventor by a large amount of experiment discovery, the quality of Lesinurad directly depends on the quality control of its synthetic intermediate, and The quality of Lesinurad intermediate is controlled must use impurity reference substance to be positioned in the foundation of analysis method, thus Lesinurad intermediate impurities are the necessitys of Lesinurad mass control.In addition, the presence of impurity is it is also possible to cause tight The side effect of weight, thus there is an urgent need in the art to effectively identify the impurity generated in Lesinurad synthesis.
Summary of the invention
The present invention is directed to the above defect existing in the prior art, provides a kind of Lesinurad intermediate impurities dimer And its preparation method and application, solve the problems, such as it is how to realize that offer can be used for miscellaneous in Lesinura intermediate synthesis process The reference substance of analysis and the monitoring of matter.
An object of the present invention technical scheme is that, a kind of Lesinurad intermediate impurities Dimer, the structural formula of the dimer is as shown in following formula I：
Above-mentioned Lesinurad intermediate impurities dimer of the invention is the present inventor different with 4- cyclopropyl -1- naphthalene Found during thiocyanates and formyl hydrazine reaction synthetic intermediate containing unknown impuritie, and simultaneously due to the intermediate itself Unstable to be difficult to purify, this just needs the unknown impuritie that will contain to bring into subsequent product, and causing need to be pure by recrystallizing Change to improve quality, directly affects the control of yield and impurity.In the present invention by largely researching and analysing, it was found that this is not The structural formula for knowing impurity is that the dimer also can just be corresponded to 4- cyclopropyl -1- in the form of dimer, and by analysis Found during naphthalenylisothiocyanate and formyl hydrazine reaction synthetic intermediate containing unknown impuritie, to realize effective The reference substance of the impurity is provided, effectively to the control of the impurity and analysis, is conducive to the quality requirement for improving product, avoids because being somebody's turn to do The presence of impurity and the processes such as the recrystallization carried out and purifying, are conducive to the yield and production efficiency that improve product.That is, Lesinurad intermediate impurities dimer of the present invention is the required reference substance for monitoring Lesinurad intermediate and product quality, energy The impurity generated in enough effectively identification Lesinurad intermediate synthesis, to control the drug quality of Lesinurad.
The second object of the present invention is to what is be achieved by the following technical programs, a kind of Lesinurad intermediate impurities The preparation method of dimer, this approach includes the following steps：
Contain type I compound Lesinurad intermediate impurities two for what II compound of formula and formylhydrazine were reacted III compound of formula of polymers, then by column chromatography for separation, isolate corresponding type I compound, obtain structure shown in formula I formula Lesinurad intermediate impurities dimer；
It is the dominating process route for generating the dimer impurity due to carrying out reaction process with II compound of formula and formylhydrazine, The impurity component can be contained in the intermediate of III compound of formula, by direct column chromatography for separation, can efficiently separate out should Dimer impurity can also guarantee preferable purity Coriolis mass requirement, realize the control point of the intermediate as Lesinurad product Analysis, and this method has product extraction convenient, is conducive to practical operation, without in addition increasing the requirement such as corresponding equipment and raw material.
In the preparation method of above-mentioned Lesinurad intermediate impurities dimer, preferably, in III compound of the formula The content of Lesinurad intermediate impurities dimer is 1%~6%.The content of impurity generally in III compound of formula is logical Cross less, and the impurity content of the intermediate is relatively high, illustrates to can be directly used in the intermediate that original reaction obtains It is directly isolated to obtain, can not consider the synthesis process in its source, be conducive to needs of production, can be avoided because of the dimer only It is impurity there are content low the phenomenon that being not readily separated out, the content for controlling the dimer impurity in reaction process is generally made to exist 5% hereinafter, can guarantee directly from containing the dimer impurity is isolated as reference substance effect in midbody product, and Also it can guarantee the purity requirement of the impurity separated itself.
In the preparation method of above-mentioned Lesinurad intermediate impurities dimer, preferably, the column chromatography for separation is adopted With silica gel column chromatography, the silica gel column chromatography uses the spherical silica-gel of 200~300 mesh；The elution that the silica gel column chromatography uses Liquid is the mixed liquor of ethyl acetate and normal hexane.Be conducive to elution separation, the separation of formula III compound and the dimer impurity Phenomenon becomes apparent from, and is convenient for stepwise elution, the content of the impurity in the further eluent containing dimer impurity for guaranteeing elution And quality requirement, it is the subsequent impurity quality requirement that high-purity is more efficiently provided, avoids excessive impurity purification process.As Further preferred, the mass ratio of the ethyl acetate and normal hexane is 1：10~1：1.
In the preparation method of above-mentioned Lesinurad intermediate impurities dimer, the corresponding reaction is according to general synthesis Process conditions guarantee the phase generated in the effective progress and the synthesis and synthesis process of III compound intermediate of reaction Answer impurity dimer.Here the solvent of reaction is generally carried out in organic solvent.Preferably, the reaction exists It is carried out in DMF solvent, and the temperature of the reaction is -10~30 DEG C.Make main III compound intermediate of synthesis formula, guarantees in this Mesosome is the main intermediate product in synthesis process, avoids the excessive formation of impurity, make to be unfavorable for intermediate product yield and The waste of raw material.
It, should as another embodiment in the preparation method of above-mentioned Lesinurad intermediate impurities dimer Lesinurad intermediate impurities dimer can also synthesize to obtain by the following method, and this approach includes the following steps：
II compound of formula and hydrazine are reacted, corresponding compound of formula I Lesinurad intermediate impurities dimerization is obtained Object；
By directly with II compound of formula and hydrazine (hydrazine is also known as hydrazine) for raw material, can one-step synthesis method, obtain phase The advantages of dimer impurity compound answered has process route short, is convenient for operation, and the raw material due to being used in reaction process It is relatively fewer, the generation of unnecessary other impurities can be also reduced, the dimerization for effectively synthesizing high-purity quality requirement is made Object impurity, yield and purity Coriolis mass requirement with higher.
In the preparation method of above-mentioned Lesinurad intermediate impurities dimer, preferably, the reaction is non-aqueous It is carried out in soluble solvent.Make reaction can be mild progress, be conducive to operation.
In the preparation method of above-mentioned Lesinurad intermediate impurities dimer, preferably, described water-insoluble molten Agent is DMF, and the temperature of the reaction is -10~20 DEG C.Reaction condition is mild, allow at a lower temperature it is ensured that Effective progress of reaction, is conducive to keep the safety in production.
In the preparation method of above-mentioned Lesinurad intermediate impurities dimer, for the use of raw material in reaction process Amount ratio can adjust according to actual needs, according to general reaction molar equivalent.Preferably, preferably making the formula II The molar ratio of compound and hydrazine (hydrazine is also known as hydrazine) is 1：1.0~2.0.Can either react fully reaction, and will not make At the excessive waste of raw material.
The third object of the present invention technical scheme is that, a kind of Lesinurad intermediate impurities The application of dimer, if above-mentioned Lesinurad intermediate impurities dimer is for the impurity check analysis in Lesinurad.
Since Lesinurad intermediate impurities dimer of the invention is one of the impurity in Lesinurad synthesis process, And the quality of Lesinurad directly depends on the quality control of its synthetic intermediate, and quality control is in the foundation of analysis method On must use corresponding impurity reference substance carry out positioning analysis, therefore can as Lesinurad mass control and analyze Impurity reference substance in journey carries out the necessity of check analysis, and the impurity dimer and accurately identification point are effectively managed in realization Analysis, advantageously reduces the serious side effects that the impurity may cause, improves the drug effect safety of drug.
In conclusion compared with prior art, the present invention having the following advantages that：
1. impurity dimer of the invention can be realized offer for impurity in Lesinura intermediate synthesis process Analysis and monitoring, effectively provide the reference substance of the impurity, are conducive to the quality requirement for improving Lesinura intermediate and product, Avoid because the impurity there are due to the processes such as the recrystallization that carries out and purifying, be conducive to the yield and production efficiency that improve product.
2. the synthetic method of impurity dimer has the advantages that simple process and impurity dimerization that is easily operated, and obtaining Object has the demanding effect of purity Coriolis mass.
Specific embodiment
Below by specific embodiment, the technical solutions of the present invention will be further described, but the present invention is simultaneously It is not limited to these embodiments.
Embodiment 1
II compound 4- cyclopropyl -1- naphthalenylisothiocyanate (LES1) of 25g formula, 10g formylhydrazine are added in reaction flask, DMF solvent 100mL is added, then, control bath temperature is stirred to react 5h under conditions of 20~30 DEG C, and reaction terminates Afterwards, reaction solution is slowly poured onto the 500mL ice water under stirring, is further continued for stirring 1h, carries out abundant crystallization, make to have a large amount of solid Body is precipitated, and after filtering, obtains just obtaining III compound (LES5) of Lesinura intermediate formula accordingly.It should by analysis Contain I compound L esinurad intermediate impurities dimer of corresponding in III compound (LES5) of Lesinura intermediate formula.It should The content of Lesinurad intermediate impurities dimer is between 1%~6% in III compound of formula.
Embodiment 2
II compound 4- cyclopropyl -1- naphthalenylisothiocyanate (LES1) of 25g formula, 11g formylhydrazine are added in reaction flask, DMF solvent 100mL is added, then, control bath temperature is stirred to react 6h, reaction knot under conditions of -10~10 DEG C Reaction solution is slowly poured onto the 500mL ice water under stirring by Shu Hou, is further continued for stirring 1h, is carried out abundant crystallization, makes to have a large amount of Solid is precipitated, and after filtering, obtains just obtaining III compound (LES5) of Lesinura intermediate formula accordingly.It should by analysis Contain I compound L esinurad intermediate impurities dimer of corresponding in III compound (LES5) of Lesinura intermediate formula.It should The content of Lesinurad intermediate impurities dimer is between 1%~6% in III compound of formula.
Embodiment 3
Prepare a glass column, the inside loads the silica gel (200~300 mesh) of 200g, and silica gel therein is spherical silica-gel, takes The LES5 solid that 10g embodiment 1 obtains is uniformly mixed with 20g silica gel (200~300 mesh), is put into the top of above-mentioned glass column. (ethyl acetate is 1 with n-hexane weight ratio to the eluent 1 of configuration 500mL:6) and configuration 1000mL 2 (ethyl acetate of eluent It is 1 with n-hexane weight ratio:4) it, is eluted respectively with eluent 1 and eluent 2, carries out eluting it switching to eluent 2 Afterwards, start to carry out the monitoring of TLC thin-layer chromatography, start switching when there is the single-point of corresponding " dimer " impurity compound and collect Corresponding eluent merges to contain and is somebody's turn to do " dimer " until the single-point for being somebody's turn to do " dimer " impurity compound disappears substantially All eluents of impurity compound single-point, are concentrated to dryness at 40~60 DEG C, just obtain compound of formula I Lesinurad intermediate impurities dimer (referred to as " dimer " impurity) 0.6g, purity >=98%.
Obtained compound of formula I Lesinurad intermediate impurities dimer is subjected to corresponding structural analysis, concrete analysis As a result as follows：
HRMS：Calcd for C28H26N4S2482.16 found 482.1487.
1H-NMR(400M,DMSO-d6)δ:10.07 (br, 1H, NH), 9.87 (br, 1H, NH), 7.26-8.43 (m, 6H, ArH),2.39-2.50(m,1H,CH),1.07-1.10(m,2H,CH2),0.73-0.77(m,2H,CH2)。
Embodiment 4
Prepare a glass column, the inside loads the silica gel (200~300 mesh) of 200g, and silica gel therein is spherical silica-gel, takes The LES5 solid that 10g embodiment 2 obtains is uniformly mixed with 20g silica gel (200~300 mesh), is put into the top of above-mentioned glass column. (ethyl acetate is 1 with n-hexane weight ratio to the eluent 1 of configuration 500mL:10) and configuration 1000mL (the acetic acid second of eluent 2 Ester and n-hexane weight ratio are 1:5) it, is eluted with eluent 1 and eluent 2, is eluted switching to eluent 2 respectively Later, start to carry out the monitoring of TLC thin-layer chromatography, start switching when there is the single-point of corresponding " dimer " impurity compound and receive Collect corresponding eluent, until the single-point for being somebody's turn to do " dimer " impurity compound disappears substantially, merges to contain and be somebody's turn to do " dimerization All eluents of object " impurity compound single-point, are concentrated to dryness at 40~60 DEG C, just obtain compound of formula I Lesinurad intermediate impurities dimer (referred to as " dimer " impurity) 0.52g, purity >=98.5%.
Obtained compound of formula I Lesinurad intermediate impurities dimer is subjected to corresponding structural analysis, concrete analysis As a result consistent with the analysis result of HRMS and 1H-NMR (400M, DMSO-d6) δ in embodiment 3.
Embodiment 5
Formula II compound 4- cyclopropyl -1- naphthalenylisothiocyanate (LES1) 25g, hydrazine (also known as hydrazine) 2g are added and reacted In bottle, DMF100mL is added, then, reaction 1h is carried out under the conditions of the temperature of 0~5 DEG C of bath temperature of control, is just rich in The reaction solution of compound of formula I Lesinurad intermediate impurities dimer (referred to as " dimer "), (is washed using silica gel column chromatography De- liquid uses the weight ratio of ethyl acetate and n-hexane for 1:4), merge all eluents containing the dimer impurity single-point, It is concentrated to dryness under conditions of 40~60 DEG C, obtains the Lesinurad intermediate impurities dimer of corresponding compound of formula I 21g, purity >=98%.
The compound of formula I Lesinurad intermediate impurities dimer that the present embodiment method is obtained carries out corresponding structure Analysis, concrete analysis result are as follows：
HRMS：Calcd for C28H26N4S2482.16 found 482.1487.
1H-NMR(400M,DMSO-d6)δ：10.06 (br, 1H, NH), 9.87 (br, 1H, NH), 7.29-8.33 (m, 6H, ArH),2.36-2.51(m,1H,CH),1.08-1.10(m,2H,CH2),0.74-0.79(m,2H,CH2)。
Equally, illustrate also be effectively obtained corresponding dimer impurity, and the impurity using direct synthetic method The purity of product is also higher.
Embodiment 6
Formula II compound 4- cyclopropyl -1- naphthalenylisothiocyanate (LES1) 25g, hydrazine (also known as hydrazine) 3.2g are added anti- It answers in bottle, adds DMF solvent 100mL, then, carry out reaction 1.0h under the conditions of the temperature of 20~30 DEG C of bath temperature of control, The reaction solution rich in compound of formula I Lesinurad intermediate impurities dimer (referred to as " dimer ") is just obtained, using silica gel (eluent uses the weight ratio of ethyl acetate and n-hexane for 1 to column chromatography:6), merge the institute containing the dimer impurity single-point There is eluent, be concentrated to dryness under conditions of 40~60 DEG C, obtains the Lesinurad intermediate of corresponding compound of formula I Impurity dimer 22g, purity >=98.5%.
Obtained compound of formula I Lesinurad intermediate impurities dimer is subjected to corresponding structural analysis, concrete analysis As a result consistent with the analysis result of HRMS and 1H-NMR (400M, DMSO-d6) δ in embodiment 5.
Embodiment 7
Formula II compound 4- cyclopropyl -1- naphthalenylisothiocyanate (LES1) 25g, hydrazine (also known as hydrazine) 6.4g are added anti- It answers in bottle, adds DMF solvent 100mL, then, carry out reaction 1.5h under the conditions of the temperature of 15~20 DEG C of bath temperature of control, The reaction solution rich in compound of formula I Lesinurad intermediate impurities dimer (referred to as " dimer ") is just obtained, using silica gel (eluent uses the weight ratio of ethyl acetate and n-hexane for 1 to column chromatography:4), merge the institute containing the dimer impurity single-point There is eluent, be concentrated to dryness under conditions of 40~60 DEG C, obtains the Lesinurad intermediate of corresponding compound of formula I Impurity dimer 21.2g, purity >=98.2%.
Obtained compound of formula I Lesinurad intermediate impurities dimer is subjected to corresponding structural analysis, concrete analysis As a result consistent with the analysis result of HRMS and 1H-NMR (400M, DMSO-d6) δ in embodiment 5.
The corresponding dimer that above-described embodiment obtains is randomly selected to be compareed as the reference substance of Lesinurad intermediate Effect explanation, come show of the invention two take object can be effectively used for Lesinurad intermediate detection in check analysis and The characteristic of quality monitoring.
The Lesinurad intermediate (LES5) that the method for above-described embodiment 1 is obtained carries out liquid chromatographic detection analysis, inspection Survey result appearance situation it is as shown in table 1 below, wherein be in table 1 in the HPLC atlas analysis of LES5 the retention time at each peak and Relative area information data.
Table 1：
Each peak data information shows wherein from above-mentioned table 1, the chromatographic peak serial number 5 of Lesinurad intermediate LES5, such as The chromatographic peak serial number 4 of the appearance of compound dimer impurity shown in Formulas I.
The Lesinurad intermediate impurities dimer (referred to as " dimer ") for the compound of formula I that above-described embodiment 3 is obtained Liquid chromatographic detection analysis is carried out, chromatography detection and analysis condition is consistent with the detection and analysis condition of above-mentioned LES5, testing result Appearance situation it is as shown in table 2 below, wherein be the retention time and opposite face at each peak in the HPLC atlas analysis of LES5 in table 2 Product information data.
Table 2：
Each peak data information shows the chromatographic peak of compound dimer impurity wherein shown in formula I from above-mentioned table 2 Serial number 2.As it can be seen that the HPLC of the peak retention time of the dimer impurity and LES5 test and analyze in corresponding retention time at Impurity appearance it is consistent, illustrate dimer of the invention can effectively as the reference substance application of Lesinurad intermediate, use In analyzing and monitoring corresponding dimer impurity, the quality requirement of product is improved.
In summary the HPLC of each example and Tables 1 and 2 tests and analyzes the result of data as it can be seen that Lesinurad of the invention Intermediate " dimer " impurity (compound dimer shown in formula I) can be identified effectively to be generated in Lesinurad intermediate Impurity, and its content in Lesinurad intermediate is calculated, to control the drug matter of final finished Lesinurad Amount.
Specific embodiment described in the present invention only illustrate the spirit of the present invention by way of example.The neck of technology belonging to the present invention The technical staff in domain can make various modifications or additions to the described embodiments or replace by a similar method In generation, however, it does not deviate from the spirit of the invention or beyond the scope of the appended claims.
It is skilled to this field although present invention has been described in detail and some specific embodiments have been cited For technical staff, as long as it is obvious for can making various changes or correct without departing from the spirit and scope of the present invention.

Claims (10)

1. a kind of Lesinurad intermediate impurities dimer, which is characterized in that the structural formula of the dimer is as shown in following formula I：
2. a kind of preparation method of Lesinurad intermediate impurities dimer, which is characterized in that this approach includes the following steps：
Contain type I compound Lesinurad intermediate impurities dimer for what II compound of formula and formylhydrazine were reacted III compound of formula, then by column chromatography for separation, isolate corresponding type I compound, obtain in type I compound Lesinurad Mesosome impurity dimer；
3. the preparation method of Lesinurad intermediate impurities dimer according to claim 2, which is characterized in that the formula The content of Lesinurad intermediate impurities dimer is 1%~6% in III compound.
4. the preparation method of Lesinurad intermediate impurities dimer according to claim 2, which is characterized in that the column Chromatography uses silica gel column chromatography, and the silica gel column chromatography uses the spherical silica-gel of 200~300 mesh；The silica gel column chromatography The eluent used is the mixed liquor of ethyl acetate and normal hexane.
5. the preparation method of Lesinurad intermediate impurities dimer according to claim 4, which is characterized in that the second The weight ratio of acetoacetic ester and normal hexane is 1：10~1：1.
6. according to the preparation method of Lesinurad intermediate impurities dimer described in claim 2-5 any one, feature exists In the reaction carries out in DMF solvent, and the temperature of the reaction is -10~30 DEG C.
7. a kind of preparation method of Lesinurad intermediate impurities dimer, which is characterized in that this approach includes the following steps：
II compound of formula and hydrazine are reacted, corresponding type I compound Lesinurad intermediate impurities dimer is obtained；
8. the preparation method of Lesinurad intermediate impurities dimer according to claim 7, which is characterized in that described anti- It should be carried out in water-insoluble solvent.
9. the preparation method of Lesinurad intermediate impurities dimer according to claim 8, which is characterized in that described non- Water-soluble solvent is DMF, and the temperature of the reaction is -10~30 DEG C.
10. a kind of application of Lesinurad intermediate impurities dimer, which is characterized in that as described in claim 1 Lesinurad intermediate impurities dimer is for the impurity check analysis in Lesinurad.
CN201811081736.0A 2018-09-17 2018-09-17 A kind of Lesinurad intermediate impurities dimer and its preparation method and application Pending CN108822013A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012033601A1 (en) * 2010-08-20 2012-03-15 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Thiosemicarbazones with mdr1 - inverse activity
CN108047148A (en) * 2017-12-28 2018-05-18 北京沃邦医药科技有限公司 A kind of preparation method of the western Nader's impurity of thunder

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012033601A1 (en) * 2010-08-20 2012-03-15 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Thiosemicarbazones with mdr1 - inverse activity
CN108047148A (en) * 2017-12-28 2018-05-18 北京沃邦医药科技有限公司 A kind of preparation method of the western Nader's impurity of thunder

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
杭太俊: "《药物分析》", 31 August 2011, 人民卫生出版社 *

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Application publication date: 20181116