CN115215765A - Preparation method of kreb polymer impurity - Google Patents
Preparation method of kreb polymer impurity Download PDFInfo
- Publication number
- CN115215765A CN115215765A CN202210861579.5A CN202210861579A CN115215765A CN 115215765 A CN115215765 A CN 115215765A CN 202210861579 A CN202210861579 A CN 202210861579A CN 115215765 A CN115215765 A CN 115215765A
- Authority
- CN
- China
- Prior art keywords
- preparation
- polymer impurity
- polymer
- impurity
- kreb
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000012535 impurity Substances 0.000 title claims abstract description 74
- 229920000642 polymer Polymers 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- ONFDBEJIGUEGNT-UHFFFAOYSA-N [5-(4-cyanophenoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl acetate Chemical compound CC(=O)OCC1=CC(OC2=CC=C(C=C2)C#N)=CC=C1B1OC(C)(C)C(C)(C)O1 ONFDBEJIGUEGNT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000001035 drying Methods 0.000 claims abstract description 9
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 239000003208 petroleum Substances 0.000 claims description 20
- 238000004809 thin layer chromatography Methods 0.000 claims description 20
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000002386 leaching Methods 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000012544 monitoring process Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000003929 acidic solution Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 10
- 238000011160 research Methods 0.000 abstract description 8
- 239000013558 reference substance Substances 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 13
- 239000002994 raw material Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 206010012438 Dermatitis atopic Diseases 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- -1 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid Chemical compound 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 2
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- USZAGAREISWJDP-UHFFFAOYSA-N crisaborole Chemical compound C=1C=C2B(O)OCC2=CC=1OC1=CC=C(C#N)C=C1 USZAGAREISWJDP-UHFFFAOYSA-N 0.000 description 1
- 229950008199 crisaborole Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of drug synthesis, and particularly discloses a preparation method of a kreb polymer impurity. The preparation method comprises the following steps: carrying out polymerization reaction on 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester under an acidic condition, and extracting, drying, concentrating and purifying after the reaction is finished to obtain a polymer impurity A. The polymer impurity A with the purity of more than 97 percent and the yield of more than 75 percent is prepared by a specific synthesis process, can be used as a related substance reference substance, solves the problem of the source of the impurity reference substance in the Cliboro, and has very important significance for the quality control of the Cliboro and the subsequent preparation research.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of a kreb polymer impurity.
Background
Crisaborol (Crisaborole), chemical name 4- [ (1,3-dihydro-1-hydroxy-2,1-benzoxaborolan-5-yl) oxy ] benzonitrile, structural formula:
is a novel, non-hormonal, topical, anti-inflammatory phosphodiesterase 4 (PDE 4) inhibitor, selectively targets over-activated phosphodiesterase 4 (PDE 4) in atopic dermatitis, reduces the production of inflammatory cytokines, alleviates the symptoms of atopic dermatitis, and is useful for treating fungal infections, more particularly onychomycosis and/or dermatophytic infections. The drug was approved by the U.S. Food and Drug Administration (FDA) for marketing in 2016, developed by Anacor pharmaceutical Inc. and responsible for marketing in the United states, under the trade name of
Compared with the existing therapeutic drugs, the Kelibuo has higher curative effect and safety, and particularly is used for the indications of children aged 2 years and older, thus filling up the unmet clinical treatment requirement of atopic dermatitis of children in China.
According to patent documents (CN 108047261, WO2018013655, US 2020062785) and non-patent documents (Wang Qishuai, etc.. Cliboron synthesis process research [ J ]. Chemicals 2020, 42 (6): 722-725), the current main synthesis methods of Cliboron are as follows:
in the preparation process of the krebs, it is found that polymer impurity A is easily generated in the process of preparing the krebs by using 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester (compound 4) through a retaining ring under an acidic condition, and the impurity is not easily removed in the refining process (on impurity comparison product purchase websites such as TLC, QCC and the like, the compound is known in the list of substances related to the krebs), the quality of the krebs finished product is seriously influenced, and therefore, the quality of the krebs needs to be controlled. High-purity impurities are required to be used as reference substances or standard substances of related substances in the quality control process. The compound shown in the formula (I) is a polymer impurity A of Cliborol, and a synthesis method thereof is not reported in the literature at present, but high importance should be paid to the quality research and the preparation research as a relatively important related substance.
Therefore, the research and development of a preparation method of the compound shown in the formula (I) with high yield and purity has very important significance on the quality control of the clironic borrelide and the subsequent preparation research.
Disclosure of Invention
In view of the above, the invention provides a preparation method of krebs polymer impurities, which has the advantages of few steps, simple operation, mild reaction conditions, high yield and high purity.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method of making a polymeric impurity of kreb, comprising the steps of:
2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester (prepared according to the method of 1.2.1-1.2.4 in the literature (Wang Qishuai et al. Cliborolo Synthesis Process research [ J ]. Chemicals 2020, 42 (6): 722-725)) is subjected to polymerization reaction under acidic conditions, and after the reaction is finished, the polymer impurity A shown in the formula (I) is obtained through extraction, drying, concentration and purification:
the structural formula of the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester is as follows:
compared with the prior art, the preparation method provided by the invention has the following advantages:
the invention provides a preparation method of kresoxim polymer impurities, which takes 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester as a raw material to carry out polymerization reaction in a specific acid solution, thereby effectively reducing the occurrence of side reactions and improving the conversion rate of a target product. According to the invention, the polymer impurity A shown in the formula (I) with the purity of more than 97% and the yield of more than 75% is prepared by a specific synthesis process, can be used as a related substance reference substance, solves the problem of the source of the impurity reference substance in Clibolo, and has very important significance for the quality control of Clibolo and the research of subsequent preparations.
Preferably, the preparation method of the kroll polymer impurity A comprises the following steps:
the method comprises the following steps: stirring and reacting 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester, an acidic solution and acetonitrile at 20-30 ℃ for 12-18 h to obtain a reaction solution containing a polymer impurity A shown in a formula (I);
step two: concentrating the reaction solution to remove an organic solvent acetonitrile, adding ethyl acetate for extraction, collecting an organic phase, and drying and concentrating the organic phase through anhydrous sodium sulfate to obtain a crude product of polymer impurities;
step three: and (3) purifying the crude polymer impurity by column chromatography to obtain a polymer impurity A shown in the formula (I).
The preferable reaction conditions can ensure that the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester fully reacts under the acidic condition, the conversion rate is improved, and the purity of the product is improved through extraction, drying, concentration and purification, so that the prepared polymer impurities meet the use requirements of a reference substance.
Preferably, the acidic solution is 0.085wt% phosphoric acid aqueous solution (85 wt% phosphoric acid is diluted 1000 times with water, which is not described in detail below).
Preferably, the ratio of the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester to the 0.085wt% phosphoric acid aqueous solution is 1g: (100-200) mL.
The preferred ratio of the reaction raw materials can improve the conversion rate of the raw materials, reduce the occurrence of side reactions, and improve the yield and purity of the polymer impurity A represented by the formula (I).
Preferably, the solvent is acetonitrile, and the ratio of 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester to acetonitrile is 1g: (100-200) mL.
The preferable solvent is favorable for dissolving the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester, so that the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester is fully mixed with 0.085wt% phosphoric acid aqueous solution, the conversion rate of raw materials is improved, the occurrence of side reactions is reduced, the smooth reaction is promoted, and the reaction rate is improved.
Preferably, the volume of the added ethyl acetate (in mL) is 10 to 20 times of the mass (in g) of the pinacol ester of 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid, that is, the ratio of the ethyl acetate to the pinacol ester of 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid is (10 to 20) mL:1g of the total weight of the composition.
The preferred extractant has high selectivity, can fully extract the polymer impurity A shown in the formula (I) in the reaction liquid into an organic phase, and greatly improves the purity and the yield of a target product.
Preferably, the column chromatography uses a mixed solvent of petroleum ether (with a boiling range of 60-90 ℃, which is not described below) and ethyl acetate as an eluent, and the volume ratio of the petroleum ether to the ethyl acetate is 10:1 and 5:1 elution is carried out sequentially.
Preferably, the filler of the column chromatography is silica gel with 100 meshes to 200 meshes.
The preferred filler can fully adsorb the polymer impurity A shown in the formula (I), and then the target product is separated from the impurity by using a specific leacheate, so that the purity and the yield of the target product are greatly improved.
Further preferably, the specific process of elution is as follows: step 1, adopting a volume ratio of 10:1, leaching the mixed solvent of petroleum ether and ethyl acetate, and discarding the leacheate after the impurities are completely eluted; step 2, adopting a volume ratio of 5:1, eluting the mixed solvent of petroleum ether and ethyl acetate, monitoring by thin-layer chromatography, and collecting eluent.
The leaching process is monitored by Thin Layer Chromatography (TLC), and the volume ratio of developing solvent of the TLC is 5:1 of petroleum ether and ethyl acetate.
Preferably, the concentration conditions are: the temperature is 30-35 ℃, and the vacuum degree is less than or equal to 0.09MPa.
According to the preparation method of the kresoxim polymer impurity A, the used reagents are common reagents, the production cost is low, the operation is simple, the test safety is high, the three wastes are less, and the preparation method is environment-friendly. The yield of the prepared polymer impurity A shown in the formula (I) can reach 78.8%, the HPLC purity is 97.25%, and the use requirement of a reference substance can be completely met.
Drawings
In order to more clearly illustrate the technical solution of the present invention, the drawings obtained in embodiment 1 will be briefly introduced below, and the drawings described below are only results corresponding to some embodiments of the present invention and are not intended to limit the scope of the present invention as claimed.
FIG. 1 is an HPLC chromatogram of impurity A of the polymer prepared in example 1 of the present invention;
FIG. 2 shows the impurity A of the polymer obtained in example 1 of the present invention 1 HNMR spectrogram;
FIG. 3 shows the polymer impurity A obtained in example 1 of the present invention 13 CNMR spectrogram.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The petroleum ether used in the following examples is a petroleum ether having a boiling range of 60 ℃ to 90 ℃.
Example 1
The embodiment provides a preparation method of a kreb polymer impurity a, which comprises the following steps:
the method comprises the following steps: dissolving 1.0g of 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester (prepared by the method of 1.2.1-1.2.4 in a literature (Wang Qishuai, etc.. Cliboron synthetic process research [ J ]. Chemicals, 2020, 42 (6): 722-725)) in 100mL of acetonitrile, adding 100mL of 0.085wt% phosphoric acid aqueous solution, controlling the temperature to 25 +/-1 ℃ and reacting for 16h to obtain a reaction solution containing the polymer impurity A shown in the formula (I);
step two: concentrating the reaction solution at the temperature of 30 ℃ and the vacuum degree of 0.09MPa to remove acetonitrile, adding 15mL of ethyl acetate after concentration, stirring for 15min, standing, separating liquid, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, and concentrating at the temperature of 30 ℃ and the vacuum degree of 0.09MPa to obtain a crude product of polymer impurities;
step three: and (3) carrying out silica gel column chromatography on the crude product of the polymer impurities, wherein the volume ratio of the crude product to the crude product is 10:1, leaching the mixed solvent of petroleum ether and ethyl acetate, and discarding the leacheate after the impurities are completely eluted; and then adopting a volume ratio of 5:1, eluting the mixed solvent of petroleum ether and ethyl acetate, monitoring by thin-layer chromatography, and collecting eluent. Wherein the particle size of the silica gel is 100-200 meshes, the elution process is monitored by thin-layer chromatography (TLC), and the volume ratio of a thin-layer chromatography developing agent is 5:1, a mixed solvent of petroleum ether and ethyl acetate. The collected leacheate was concentrated to dryness at 30 ℃ under a vacuum of 0.09MPa to obtain 1.09g of the polymer impurity A represented by the formula (I) as a white solid at a yield of 78.8% with a purity of 97.25% by area normalization (see FIG. 1).
The HPLC detection method of the obtained polymer impurity A is as follows:
and (3) chromatographic column: YMC Triart C18 ExRS 4.6 × 250mm 5 μm,8nm;
mobile phase:
flow rate: 1.0mL/min; wavelength: 230nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution;
t R ：16.5min；t r (raw material) ：40.8min(RRT0.40)；
Test solution: 0.5mg/mL (acetonitrile).
Example 2
The embodiment provides a preparation method of a kreb polymer impurity a, which comprises the following steps:
the method comprises the following steps: dissolving 1.0g of 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester (derived from the same source as in example 1) in 200mL of acetonitrile, adding 200mL of 0.085wt% phosphoric acid aqueous solution, and reacting for 16 hours at the temperature of 25 +/-1 ℃ to obtain a reaction solution containing a polymer impurity A shown in formula (I);
step two: concentrating the reaction solution at the temperature of 30 ℃ and the vacuum degree of 0.09MPa to remove acetonitrile, adding 15mL of ethyl acetate after concentration, stirring for 15min, standing, separating liquid, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, and concentrating at the temperature of 30 ℃ and the vacuum degree of 0.09MPa to obtain a crude product of polymer impurities;
step three: and (3) carrying out silica gel column chromatography on the crude product of the polymer impurities, wherein the volume ratio of the crude product to the crude product is 10:1, leaching the mixed solvent of the petroleum ether and the ethyl acetate, and discarding the leacheate after the impurities are completely eluted; and then adopting a volume ratio of 5:1, eluting the mixed solvent of petroleum ether and ethyl acetate, monitoring by thin-layer chromatography, and collecting eluent. Wherein the particle size of the silica gel is 100-200 meshes, the elution process is monitored by thin-layer chromatography (TLC), and the volume ratio of a thin-layer chromatography developing agent is 5:1, a mixed solvent of petroleum ether and ethyl acetate. The collected leacheate was concentrated to dryness at 30 ℃ under a vacuum of 0.09MPa to obtain 1.05g of a white solid polymer impurity A represented by the formula (I), with a yield of 75.7% and a purity of 96.95% by area normalization.
Example 3
The embodiment provides a preparation method of a kreb polymer impurity, which comprises the following steps:
the method comprises the following steps: dissolving 1.0g of 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester (the source is the same as in example 1) in 150mL of acetonitrile, adding 150mL of 0.085wt% phosphoric acid aqueous solution, and controlling the temperature to be 25 +/-1 ℃ to react for 16h to obtain a reaction solution containing the polymer impurity A shown in the formula (I);
step two: concentrating the reaction solution at the temperature of 30 ℃ and the vacuum degree of 0.09MPa to remove acetonitrile, adding 15mL of ethyl acetate after concentration, stirring for 15min, standing, separating liquid, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, and concentrating at the temperature of 30 ℃ and the vacuum degree of 0.09MPa to obtain a crude product of polymer impurities;
step three: and (3) carrying out silica gel column chromatography on the crude product of the polymer impurities, wherein the volume ratio of the crude product to the crude product is 10:1, leaching the mixed solvent of the petroleum ether and the ethyl acetate, and discarding the leacheate after the impurities are completely eluted; then adopting a volume ratio of 5:1, eluting with a mixed solvent of petroleum ether and ethyl acetate, monitoring by thin layer chromatography, and collecting eluate. Wherein the particle size of the silica gel is 100-200 meshes, the elution process is monitored by thin-layer chromatography (TLC), and the volume ratio of a thin-layer chromatography developing agent is 5:1, a mixed solvent of petroleum ether and ethyl acetate. The collected leacheate is concentrated to be dry under the conditions that the temperature is 30 ℃ and the vacuum degree is 0.09MPa, and finally, 1.06g of polymer impurity A shown in the formula (I) of white solid is obtained, the yield is 76.5%, and the purity is 97.10% by an area normalization method.
The polymer impurity a represented by the formula (I) obtained in example 1 was analyzed by hydrogen spectroscopy and carbon spectroscopy, and the results are shown in fig. 2 to 3, and the analysis results are as follows:
1 HNMR(400Hz，CDCl 3 )：δ：8.34(1H)，7.98～7.62(5H)，7.13～7.03 (6H)，6.44(2H)，5.72(1H)，5.24(2H)，4.24～4.18(1H)，2.15～2.11 (6H)
13 CNMR(400Hz，CDCl 3 )δ：172.02，171.01，160.78，160.24， 159.05，156.77，142.32，139.73，136.85，134.27，134.19，130.88， 128.75，120.65，119.32，119.02，118.78，118.61，118.44，118.10， 106.89，106.39，68.17，66.28，30.30，28.86，23.68，22.92，21.01， 20.97。
it can be seen that the assignment of hydrogen in the hydrogen spectrum of the target product prepared in example 1 is consistent with that of the polymer impurity a, and the assignment of carbon in the carbon spectrum is consistent with that of the polymer impurity a, which indicates that the structure of the target product obtained in example 1 is consistent with that of the polymer impurity a.
The results of the hydrogen spectrum analysis and the carbon spectrum analysis of examples 2 to 3 also agree with the analysis result of example 1.
In order to better illustrate the technical solution of the present invention, further comparison is made below by means of a comparative example and an example of the present invention.
Comparative example 1
The comparative example provides a method of preparing a kroll polymer impurity, comprising the steps of:
the method comprises the following steps: 1.0g of 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester (obtained in the same manner as in example 1) was dissolved in 10mL of tetrahydrofuran, and then 3.0g of concentrated hydrochloric acid (37 wt%) was added thereto, followed by reaction at 40 ℃ for 16 hours to obtain a reaction solution containing the polymer impurity A represented by the formula (I);
the specific processes of the second step and the purification are the same as those in example 1, and are not repeated, 0.36g of the target product is finally prepared, the yield is 22.8%, the purity is 85.3%, the obtained target product is detected by an HPLC method, and the relative retention time is consistent with that of the products obtained in examples 1-3.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (9)
1. A method for preparing a kreb polymer impurity is characterized in that: the preparation method comprises the following steps:
carrying out polymerization reaction on 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester under an acidic condition, and after the reaction is finished, extracting, drying, concentrating and purifying to obtain a polymer impurity A shown in a formula (I);
2. the method of producing kreb polymer impurity as claimed in claim 1, characterized in that: the preparation method comprises the following steps:
the method comprises the following steps: reacting 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester, an acidic solution and acetonitrile at the temperature of between 20 and 30 ℃ for 12 to 18 hours under stirring to obtain a reaction solution containing a polymer impurity A shown in a formula (I);
step two: concentrating the reaction solution to remove the organic solvent acetonitrile, adding ethyl acetate for extraction, collecting an organic phase, drying the organic phase by anhydrous sodium sulfate, and concentrating to obtain a crude product of polymer impurities;
step three: and (3) purifying the crude polymer impurity by column chromatography to obtain a polymer impurity A shown in the formula (I).
3. A process for the preparation of a kreb polymer impurity as claimed in claim 2, characterized in that: the acidic solution in step one is 0.085wt% phosphoric acid aqueous solution.
4. A process for the preparation of a kreb polymer impurity as claimed in claim 2, characterized in that: the ratio of the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester to 0.085wt% phosphoric acid aqueous solution in the first step was 1g: (100-200) mL.
5. A process for the preparation of a krebs polymer impurity as claimed in claim 2, wherein: the ratio of the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester to acetonitrile in step one is 1g: (100-200) mL.
6. A process for the preparation of a kreb polymer impurity as claimed in claim 2, characterized in that: the proportion of the ethyl acetate to the 2-acetoxymethyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester in the second step is (10-20) mL:1g of the total weight of the composition.
7. A process for the preparation of a kreb polymer impurity as claimed in claim 2, characterized in that: in the third step, the column chromatography is carried out according to the volume ratio of petroleum ether to ethyl acetate of 10:1 and 5:1, eluting in sequence, wherein the filler of the column chromatography is silica gel with 100-200 meshes.
8. The process for the preparation of a kreb polymer impurity as claimed in claim 7, characterized in that: the specific process of elution is as follows:
step 1, adopting a volume ratio of 10:1, leaching the mixed solvent of petroleum ether and ethyl acetate, and discarding the leacheate after the impurities are completely eluted;
step 2, adopting a volume ratio of 5:1, leaching the mixed solvent of petroleum ether and ethyl acetate, and collecting leacheate;
and monitoring by thin-layer chromatography (TLC) in the leaching process, wherein a developing agent of the TLC is a mixture of 5:1 of petroleum ether and ethyl acetate.
9. A process for the preparation of a kreb polymer impurity as claimed in claim 2, characterized in that: the concentration conditions in the second step are as follows: the temperature is 30-35 ℃, and the vacuum degree is less than or equal to 0.09MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210861579.5A CN115215765A (en) | 2022-07-20 | 2022-07-20 | Preparation method of kreb polymer impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210861579.5A CN115215765A (en) | 2022-07-20 | 2022-07-20 | Preparation method of kreb polymer impurity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115215765A true CN115215765A (en) | 2022-10-21 |
Family
ID=83613625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210861579.5A Pending CN115215765A (en) | 2022-07-20 | 2022-07-20 | Preparation method of kreb polymer impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115215765A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115932148A (en) * | 2023-01-03 | 2023-04-07 | 上海明捷医药科技有限公司 | Method for detecting pinacol residual quantity in Clibolol bulk drug |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018150327A1 (en) * | 2017-02-14 | 2018-08-23 | Wavelength Enterprises Ltd | Crisaborole production process |
| CN113563268A (en) * | 2021-07-12 | 2021-10-29 | 河北国龙制药有限公司 | Preparation method of dexmedetomidine hydrochloride degradation impurities |
| CN114716349A (en) * | 2022-04-29 | 2022-07-08 | 武汉绿合医药科技有限公司 | Preparation method of Kelibaro impurity |
-
2022
- 2022-07-20 CN CN202210861579.5A patent/CN115215765A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018150327A1 (en) * | 2017-02-14 | 2018-08-23 | Wavelength Enterprises Ltd | Crisaborole production process |
| CN113563268A (en) * | 2021-07-12 | 2021-10-29 | 河北国龙制药有限公司 | Preparation method of dexmedetomidine hydrochloride degradation impurities |
| CN114716349A (en) * | 2022-04-29 | 2022-07-08 | 武汉绿合医药科技有限公司 | Preparation method of Kelibaro impurity |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115932148A (en) * | 2023-01-03 | 2023-04-07 | 上海明捷医药科技有限公司 | Method for detecting pinacol residual quantity in Clibolol bulk drug |
| CN115932148B (en) * | 2023-01-03 | 2024-05-17 | 上海明捷医药科技有限公司 | Detection method for pinacol residue in clenbuterol bulk drug |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20150299241A1 (en) | Method for preparing highly pure doxorubicin | |
| CN115215765A (en) | Preparation method of kreb polymer impurity | |
| CN111410658B (en) | Impurity A and impurity B of midazolam or pharmaceutical composition thereof and application thereof | |
| CN1268631C (en) | Technique for preparing general flavone of Chinese globeflower with short petal some medicinal substances in high purity | |
| CN108997349B (en) | Preparation method of epinastine related substances | |
| CN111747881A (en) | Two isopentenyl substituted indole alkaloids with alpha-glucosidase inhibition effect, and preparation method and application thereof | |
| CN102659884B (en) | Gemcitabine hydrochloride purifying method | |
| CN108473523B (en) | Preparation method of epirubicin hydrochloride and intermediate thereof | |
| CN111747857B (en) | Amino sugar compounds, preparation method and application thereof | |
| CN110698532B (en) | Method for extracting sea cucumber saponin Cladoloside A | |
| CN112028887B (en) | Penehyclidine hydrochloride impurity and preparation method thereof | |
| EP3619215B1 (en) | Process to convert crude ascomycin into purified pimecrolimus | |
| CN108912018B (en) | Preparation method and application of impurity compound in key intermediate for synthesizing sulpiride | |
| WO2023000636A1 (en) | Method for synthesis of (3-fluorooxetan-3-yl)methyl 4-methylbenzenesulfonate | |
| CN112321642A (en) | Ruidexiwei related substance and preparation method and application thereof | |
| CN114213496A (en) | Method for separating lanosterol and dihydrolanosterol | |
| Shaji et al. | Synthesis of 1-octacosanol from 1, 12 dodecanediol and cetyl alcohol | |
| CN114685448A (en) | Synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl) -amide | |
| CN109096273A (en) | The method for separating and preparing of mezlocillin sodium impurity C, D and F | |
| CN105732539A (en) | Pramipexole oxidated impurity, preparation and separation method therefor and application of pramipexole oxidated impurity | |
| CN109734760A (en) | A kind of preparation method of doractin impurity | |
| CN114380666B (en) | Industrial extraction method of cannabidiol | |
| CN114716391B (en) | Methanazole impurity and preparation method and application thereof | |
| CN114315779B (en) | Preparation and application of alpha-pyrone derivatives with blood sugar reducing effect | |
| CN109490448A (en) | A kind of preparation method of digoxin standard substance |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20221021 |
|
| RJ01 | Rejection of invention patent application after publication |