CN114213437A - Central control method for 1-isopropylpyrazole-5-boronic acid pinacol ester synthesis reaction - Google Patents
Central control method for 1-isopropylpyrazole-5-boronic acid pinacol ester synthesis reaction Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 66
- ZKZJXVGTTZXHGX-UHFFFAOYSA-N 1-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CC(C)N1N=CC=C1B1OC(C)(C)C(C)(C)O1 ZKZJXVGTTZXHGX-UHFFFAOYSA-N 0.000 title claims abstract description 53
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 29
- 239000007789 gas Substances 0.000 claims description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000004817 gas chromatography Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
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- ZYGAMJLTPLERBC-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid propan-2-ol Chemical compound B(O)(O)OC(C)(C)C(C)(C)O.C(C)(C)O ZYGAMJLTPLERBC-UHFFFAOYSA-N 0.000 description 6
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- C—CHEMISTRY; METALLURGY
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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Abstract
The invention provides a central control method for a synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, belonging to the field of gas phase analysis. The invention adopts a DB-624 chromatographic column, the temperature rise program is that the initial temperature is 60-80 ℃, the temperature is kept for 1-5 min, then the temperature rise speed is increased to 200-250 ℃ at the speed of 10-20 ℃/min, and the temperature is kept for 10-20 min, therefore, the invention can effectively separate various conventional solvents and various raw materials and products involved in the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, thereby realizing the central control of the reaction system of the synthesis method of the various 1-isopropylpyrazole-5-boronic acid pinacol esters.
Description
Technical Field
The invention relates to a gas phase detection method, in particular to a central control method for 1-isopropylpyrazole-5-boronic acid pinacol ester synthesis reaction.
Background
Sickle Cell Disease (SCD) is a lifelong inherited blood disorder caused by genetic mutations in the beta chain of hemoglobin, resulting in abnormal sickle hemoglobin (HbS). In the deoxygenated state, HbS has a tendency to polymerize or bind together, forming a rigid rod-like structure within the red blood cells. The polymeric rod-like structure makes the red blood cells sickle-shaped and inflexible, and can lead to clogging of capillaries and small blood vessels. From childhood, SCD patients often suffer from psychological and physical disabilities due to unpredictable and recurrent episodes of severe pain or crisis resulting from the inability of blood to flow smoothly to the organs. The blocked blood flow, coupled with hemolytic anemia (destruction of red blood cells), may eventually lead to multiple organ damage and early death.
Woseltantor (Compound I) is a drug developed by Global Blood therapeutics for the treatment of sickled red cell disease in patients 12 years old and older, the mechanism of action of which is an inhibitor of hemoglobin polymerization that blocks polymerization and the resultant sickling and destruction of red cells.
The structural formula of Woselta is shown as the following formula:
according to the literature, 1-isopropyl pyrazole-5-boronic acid pinacol ester (compound II) is reported to be an important intermediate for synthesizing Woselta.
In the prior art, there is no route for synthesizing the compound, and the applicant has designed the following route:
in the step 1, the method comprises the following steps of,
in the step 2, the step of mixing the raw materials,
in the actual production process, a manufacturer can use different reaction conditions according to actual requirements and production conditions, especially different reaction solvents can be selected, for example, the reaction solvent in step 1 can be a plurality of solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, etc., however, different solvents may affect the peak of the raw material in the detection, thereby affecting the judgment of the reaction progress, and the peak-off time between part of the raw material, impurities and the solvent is relatively close, so that the raw material, the impurities and the solvent are difficult to be effectively separated. Therefore, in the prior art, different central control detection methods are often needed to be used for monitoring different reaction systems, which can bring heavy burden to the central control process.
In addition, the method by which the final product is prepared and the solvent used in the preparation process cannot be known in advance, and therefore, in order to check the purity of the final product, a general method for checking the purity of 1-isopropylpyrazole-5-boronic acid pinacol ester, which can be synthesized by various routes, is also required.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a general-purpose central control method that can be used for a variety of methods for synthesizing 1-isopropylpyrazole-5-boronic acid pinacol esters.
The invention provides a central control method for 1-isopropyl pyrazole-5-boronic acid pinacol ester synthesis reaction, which is characterized in that: using gas chromatography, the parameters of the gas chromatography are: the chromatographic column is a DB-624 chromatographic column, the diluent is acetonitrile, and the temperature-raising program comprises the following steps: the initial temperature is 60-80 ℃, the temperature is kept for 1-5 min, then the temperature is increased to 200-250 ℃ at the heating rate of 10-20 ℃/min, and the temperature is kept for 10-20 min.
In the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, provided by the invention, the method also has the following characteristics: wherein, the parameters of the gas chromatography are as follows: the chromatographic column is a DB-624 chromatographic column, the diluent is acetonitrile, and the temperature-raising program comprises the following steps: the initial temperature was 80 ℃ for 2min, followed by a ramp up to 240 ℃ at a ramp rate of 10 ℃/min for 20 min.
In the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, provided by the invention, the method also has the following characteristics: wherein, the gas chromatography also comprises the following parameters: the temperature of the injection port is 180-220 ℃, the temperature of the detector is 250-300 ℃, the carrier gas is nitrogen, the flow rate of the column is 0.6-0.7 mL/min, the split ratio is (8-12):1, the flow rate of the hydrogen is 25-35 mL/min, the flow rate of the air is 250-350 mL/min, and the flow rate of the tail gas is 20-30 mL/min.
In the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, provided by the invention, the method also has the following characteristics: wherein, the gas chromatography also comprises the following parameters: the injection port temperature is 200 ℃, the detector temperature is 280 ℃, the carrier gas is nitrogen, the column flow rate is 0.7mL/min, the split ratio is 10:1, the hydrogen flow rate is 30mL/min, the air flow rate is 300mL/min, and the tail gas flow rate is 25 mL/min.
In the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, provided by the invention, the method also has the following characteristics: wherein the reaction solvent used in the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester is any one of isopropanol, tetrahydrofuran, dichloromethane, ethyl acetate, methanol or acetonitrile.
In the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, provided by the invention, the method also has the following characteristics: wherein, the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester comprises the following steps:
in the step 1, the method comprises the following steps of,
in the step 2, the step of mixing the raw materials,
in the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, provided by the invention, the method also has the following characteristics: wherein, in the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, the reaction solvent in the step 1 is one or more of isopropanol, tetrahydrofuran, dichloromethane, ethyl acetate, methanol or acetonitrile, and the reaction solvent in the step 2 is tetrahydrofuran.
Action and Effect of the invention
According to the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, disclosed by the invention, as the DB-624 chromatographic column is adopted, the temperature rise program is that the initial temperature is 60-80 ℃, the temperature is kept for 1-5 min, then the temperature rise speed is increased to 200-250 ℃ at the speed of 10-20 ℃/min, and the temperature is kept for 10-20 min, various conventional solvents and various raw materials and products involved in the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester can be effectively separated, and thus the central control of the reaction system of the synthesis reaction method of the various 1-isopropylpyrazole-5-boronic acid pinacol esters can be realized.
Drawings
FIG. 1 is a gas chromatogram of a pyrazole sample in example 1 of the present invention;
FIG. 2 is a gas chromatogram of a 2-bromopropane sample from example 1 of the present invention;
FIG. 3 is a gas chromatogram of 1-isopropylpyrazole sample in example 1 of the present invention;
FIG. 4 is a gas chromatogram of an isopropanol pinacol borate sample in example 1 of the present invention;
FIG. 5 is a gas chromatogram of a sample of 1-isopropylpyrazole-5-boronic acid pinacol ester in example 1 of the present invention;
FIG. 6 is a gas chromatogram of an acetonitrile sample in example 1 of the present invention;
FIG. 7 is a gas chromatogram of a dichloromethane sample in example 1 of the present invention;
FIG. 8 is a gas chromatogram of an ethyl acetate sample in example 1 of the present invention;
FIG. 9 is a gas chromatogram of an isopropanol sample in example 1 of the present invention;
FIG. 10 is a gas chromatogram of a tetrahydrofuran sample in example 1 of the present invention;
FIG. 11 is a gas chromatogram of the mixed sample in example 1 of the present invention.
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the invention is specifically described below by combining the embodiment and the attached drawings.
In the following examples and comparative examples, the gas phase apparatus used was a GC-2010Pro gas phase apparatus with a FID detector manufactured by Shimadzu corporation, Japan, unless otherwise specified.
In the following examples and comparative examples, all the gas chromatography columns used were those produced by Agilent, unless otherwise specified.
In the following examples and comparative examples, the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester comprises the following steps, unless otherwise specified:
in the step 1, the method comprises the following steps of,
in the step 2, the step of mixing the raw materials,
in the following examples and comparative examples, pyrazole, 2-bromopropane, isopropanol pinacol borate, acetonitrile, dichloromethane, ethyl acetate, isopropanol, tetrahydrofuran were all commercially available products unless otherwise specified, and 1-isopropylpyrazole-5-boronic acid pinacol esters were prepared by a conventional method.
In the following examples and comparative examples, unless otherwise stated, the solid sample was prepared by dissolving 20mg of the sample in 1.0mL of the diluent used in the corresponding assay method, and the liquid sample was prepared by directly filtering the sample.
< example 1>
Central control method
This example provides a central control method for the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, and the specific method is shown in table 1.
TABLE 1 gas phase detection Condition Table
In this example, pyrazole-like, 2-bromopropane-like, 1-isopropylpyrazole-like, isopropanol pinacol borate-like (containing an unknown impurity and methylene chloride), 1-isopropylpyrazole-5-boronic acid pinacol ester-like, acetonitrile-like, methylene chloride-like, ethyl acetate-like, isopropanol-like, and tetrahydrofuran-like were each subjected to localization by the gas phase detection method described in Table 1. The results are shown in FIGS. 1 to 10 and Table 2, respectively.
TABLE 2 Retention time of the respective raw materials, products and solvents
| Serial number | Sample (I) | Retention time (min) |
| 1 | Pyrazole sample | 14.088 |
| 2 | 2-bromopropane sample | 6.729 |
| 3 | 1-isopropyl-pyrazoles | 13.197 |
| 4 | Isopropanol pinacol boronic acid ester sample | 16.724 |
| 5 | Unknown impurity | 27.338 |
| 6 | 1-isopropylpyrazole-5-boronic acid pinacol ester | 26.911 |
| 7 | Acetonitrile sample | 5.961 |
| 8 | Dichloromethane sample | 6.038 |
| 9 | Acetic acid ethyl ester sample | 7.128 |
| 10 | Isopropyl alcohol sample | 5.765 |
| 11 | Tetrahydrofuran-like compounds | 7.482 |
As can be seen from fig. 1-10 and table 2, the central control method provided in this example can effectively separate various raw materials, products, impurities and some solvents commonly used in the reactions involved.
In order to further verify the reliability of the central control method provided by the embodiment, the embodiment also detects the mixed sample. In this example, the preparation method of the mixed sample used was: and (3) mixing 50 mu L of the middle control solution obtained in the step (1) reaction with 50 mu L of the middle control solution obtained in the step (2). The detection results are shown in fig. 11.
As shown in fig. 11, the central control method provided in this embodiment can effectively separate each raw material, product, and impurity, and the separation degree between each peak is good, so that the reaction can be accurately controlled.
Furthermore, the central control method provided in this example is used to verify the reaction systems of various methods for synthesizing 1-isopropylpyrazole-5-boronic acid pinacol ester, so that each raw material, impurity, intermediate, product and solvent can give out peaks well, and each peak can be separated well without overlapping.
< comparative example 1>
Central control method
The comparative example provides a central control method for the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, and the specific method is shown in table 3.
TABLE 3 gas phase detection Condition Table
In this comparative example, pyrazole samples, 2-bromopropane samples, 1-isopropylpyrazole samples, isopropanol pinacol borate samples, 1-isopropylpyrazole-5-boronic acid pinacol ester samples, acetonitrile samples, dichloromethane samples, ethyl acetate samples, isopropanol samples, and tetrahydrofuran samples were each detected and localized by the gas phase detection method described in table 3, and it was found that the retention time of 2-bromopropane and the retention time of acetonitrile were very close to each other under the detection conditions, and the separation was not effective.
< comparative example 2>
Central control method
The comparative example provides a central control method for the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, and the specific method is shown in table 4.
TABLE 4 gas phase detection Condition Table
In this comparative example, pyrazole samples, 2-bromopropane samples, 1-isopropylpyrazole samples, isopropanol pinacol borate samples, 1-isopropylpyrazole-5-boronic acid pinacol ester samples, acetonitrile samples, dichloromethane samples, ethyl acetate samples, isopropanol samples, and tetrahydrofuran samples were each detected and localized by the gas phase detection method described in table 4, and it was found that the retention time of pyrazole under the detection conditions was very close to that of 1-isopropylpyrazole, and thus effective separation was not achieved.
< comparative example 3>
Central control method
The comparative example provides a central control method for the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, and the specific method is shown in table 5.
TABLE 5 gas phase detection Condition Table
In this comparative example, pyrazole samples, 2-bromopropane samples, 1-isopropylpyrazole samples, isopropanol pinacol borate samples, 1-isopropylpyrazole-5-boronic acid pinacol ester samples, acetonitrile samples, dichloromethane samples, ethyl acetate samples, isopropanol samples, and tetrahydrofuran samples were each detected and localized by the gas phase detection method described in table 5, and it was found that 1-isopropylpyrazole-5-boronic acid pinacol ester did not show a peak under the detection conditions, and thus it was not suitable as a central control method for the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester.
< comparative example 4>
Central control method
The comparative example provides a central control method for the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, and the specific method is shown in table 6.
TABLE 6 gas phase detection Condition Table
In this comparative example, pyrazole samples, 2-bromopropane samples, 1-isopropylpyrazole samples, isopropanol pinacol borate samples, 1-isopropylpyrazole-5-boronic acid pinacol ester samples, acetonitrile samples, dichloromethane samples, ethyl acetate samples, isopropanol samples, and tetrahydrofuran samples were each detected and positioned by the gas phase detection method described in Table 6, and it was found that 1-isopropylpyrazole-5-boronic acid pinacol ester could not stably form a peak under the detection conditions, that is, 1-isopropylpyrazole-5-boronic acid pinacol ester could not form a peak in some cases, and thus, the comparative example was not suitable as a method for controlling the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester.
Effects and effects of the embodiments
According to the central control method for the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, which is related in the embodiment, because a DB-624 chromatographic column is adopted, the temperature rise program is that the initial temperature is 60-80 ℃, the temperature is kept for 1-5 min, then the temperature rise rate is increased to 200-250 ℃ at the speed of 10-20 ℃/min, and the temperature is kept for 10-20 min, the central control method provided by the embodiment can effectively separate various conventional solvents and various raw materials and products related in the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester, and thus the central control of the reaction system of the synthesis reaction method of the various 1-isopropylpyrazole-5-boronic acid pinacol esters can be realized.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (8)
1. A central control method for 1-isopropyl pyrazole-5-boric acid pinacol ester synthesis reaction is characterized in that gas chromatography is used,
the parameters of the gas chromatography are:
the chromatographic column is a DB-624 chromatographic column,
the diluent is acetonitrile, and the diluent is acetonitrile,
temperature rising procedure: the initial temperature is 60-80 ℃, the temperature is kept for 1-5 min, then the temperature is increased to 200-250 ℃ at the heating rate of 10-20 ℃/min, and the temperature is kept for 10-20 min.
2. The method of claim 1, wherein the reaction is a central control method of the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, which comprises the following steps:
wherein the parameters of the gas chromatography are as follows:
the chromatographic column is a DB-624 chromatographic column,
the diluent is acetonitrile, and the diluent is acetonitrile,
temperature rising procedure: the initial temperature was 80 ℃ for 2min, followed by a ramp up to 240 ℃ at a ramp rate of 10 ℃/min for 20 min.
3. The method of claim 1, wherein the reaction is a central control method of the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, which comprises the following steps:
wherein, the gas chromatography also comprises the following parameters:
the temperature of the sample inlet is 180-220 ℃,
the temperature of the detector is 250-300 ℃,
the carrier gas is nitrogen gas,
the flow rate of the column is 0.6mL/min to 0.7mL/min,
the split ratio is (8-12) to 1,
the hydrogen flow rate is 25mL/min-35mL/min,
the air flow rate is 250mL/min-350mL/min,
the flow rate of the tail gas blowing is 20mL/min-30 mL/min.
4. The method of claim 3 for the central control of the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, wherein:
wherein, the gas chromatography also comprises the following parameters:
the temperature of the sample inlet is 200 ℃,
the temperature of the detector was 280 c,
the carrier gas is nitrogen gas,
the column flow rate was 0.7mL/min,
the split ratio is 10:1, and the weight ratio of the main components,
the flow rate of hydrogen is 30mL/min,
the air flow rate is 300mL/min,
the flow rate of the tail gas was 25 mL/min.
5. The method of claim 1, wherein the reaction is a central control method of the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester, which comprises the following steps:
wherein the parameters of the gas chromatography are as follows:
the chromatographic column is a DB-624 chromatographic column,
the diluent is acetonitrile, and the diluent is acetonitrile,
temperature rising procedure: the initial temperature is 80 ℃, the temperature is kept for 2min, then the temperature is increased to 240 ℃ at the heating rate of 10 ℃/min, the temperature is kept for 20min,
the temperature of the sample inlet is 200 ℃,
the temperature of the detector was 280 c,
the carrier gas is nitrogen gas,
the column flow rate was 0.7mL/min,
the split ratio is 10:1, and the weight ratio of the main components,
the flow rate of hydrogen is 30mL/min,
the air flow rate is 300mL/min,
the flow rate of the tail gas was 25 mL/min.
6. The method for the central control of the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester according to claim 1,
wherein the reaction solvent used in the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester is any one of isopropanol, tetrahydrofuran, dichloromethane, ethyl acetate, methanol or acetonitrile.
7. The method for the central control of the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester according to claim 1,
wherein, the synthesis reaction of the 1-isopropylpyrazole-5-boronic acid pinacol ester comprises the following steps:
in the step 1, the method comprises the following steps of,
in the step 2, the step of mixing the raw materials,
8. the method for the central control of the synthesis reaction of 1-isopropylpyrazole-5-boronic acid pinacol ester according to claim 7,
wherein the reaction solvent in the step 1 is isopropanol, and the reaction solvent in the step 2 is tetrahydrofuran.
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| CN103601749A (en) * | 2013-11-26 | 2014-02-26 | 大连联化化学有限公司 | Synthetic method of 1-alkylpyrazole-4-boronic acid pinacol ester |
| CN104478917A (en) * | 2014-12-31 | 2015-04-01 | 大连联化化学有限公司 | Synthesis method for 1-substitution-1H-pyrazol-4-boric acid pinacol ester |
| CN105669733A (en) * | 2016-01-29 | 2016-06-15 | 上海毕路得医药科技有限公司 | Synthetic method of 1-methyl-1H-pyrazole-3-boronic acid pinacol ester |
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| CN103601749A (en) * | 2013-11-26 | 2014-02-26 | 大连联化化学有限公司 | Synthetic method of 1-alkylpyrazole-4-boronic acid pinacol ester |
| CN104478917A (en) * | 2014-12-31 | 2015-04-01 | 大连联化化学有限公司 | Synthesis method for 1-substitution-1H-pyrazol-4-boric acid pinacol ester |
| CN105669733A (en) * | 2016-01-29 | 2016-06-15 | 上海毕路得医药科技有限公司 | Synthetic method of 1-methyl-1H-pyrazole-3-boronic acid pinacol ester |
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