CN116482278B - Preparation method of reference substance for detecting acyclovir - Google Patents
Preparation method of reference substance for detecting acyclovir Download PDFInfo
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- CN116482278B CN116482278B CN202310503147.1A CN202310503147A CN116482278B CN 116482278 B CN116482278 B CN 116482278B CN 202310503147 A CN202310503147 A CN 202310503147A CN 116482278 B CN116482278 B CN 116482278B
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- acyclovir
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- reference substance
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- alkali
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- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960004150 aciclovir Drugs 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000013558 reference substance Substances 0.000 title claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- NZZFYRREKKOMAT-OUBTZVSYSA-N diiodomethane Chemical group I[13CH2]I NZZFYRREKKOMAT-OUBTZVSYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 150000003834 purine nucleoside derivatives Chemical class 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a reference substance for detecting acyclovir, which aims to provide a qualified reference substance for quality control of acyclovir, wherein the reference substance is prepared by dissolving acyclovir in an organic solvent, reacting for 8-16 hours under the action of a condensing agent and alkali at the temperature of 10-100 ℃ to obtain a reaction solution containing the reference substance for detecting acyclovir, and finally purifying by a column; the synthetic method has the advantages of simple synthetic route, mild reaction conditions, low price and easy acquisition of raw materials and reagents; belonging to the technical field of organic synthesis.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a reference substance for detecting acyclovir.
Background
Acyclovir (ACV), also known as acyclovir, chemical name 9- [ (2-hydroxyethoxy) methyl ] -guanine, is a synthetic purine nucleoside analogue, is a high-efficiency spectrum antiviral drug, and was first synthesized and applied in the uk in 1981, mainly for various infections caused by herpes simplex virus, and can be used for HSV infections caused by primary or recurrent skin, mucous membranes, external genitalia infections and immunodeficiency persons. The drug is highly effective against type I and type II herpes simplex and varicella zoster virus, and has been listed as a basic therapeutic drug. The research of related substances (impurities) is an important point and a difficult point of the research of medicine quality, and the research of synthesizing and separating out impurity monomers is indispensable to the structure, toxicity and limit control of the impurity monomers.
Disclosure of Invention
In order to overcome the defects, the first aim of the invention is to provide a preparation method of a reference substance for detecting acyclovir, which takes acyclovir as a raw material, and generates the reference substance for detecting acyclovir under the action of diiodomethane and alkali.
Therefore, the technical scheme provided by the invention is that the preparation method of the reference substance for detecting acyclovir sequentially comprises the following steps:
dissolving acyclovir in an organic solvent, reacting for 8-16 hours at 10-100 ℃ under the action of condensing agent and alkali to obtain a reaction solution containing a reference substance for detecting acyclovir, and finally purifying by a column;
the mol ratio of the acyclovir to the alkali is as follows: 1:0.5-3;
the mol ratio of the acyclovir to the condensing agent is as follows: 1:0.2-2.
The reaction route of the invention is as follows:
the preparation of the compound is shown in formula 1:
formula 1.
Further, in the preparation method of the control for detecting acyclovir, the molar ratio of acyclovir to alkali is 1:1.5.
Furthermore, in the preparation method of the control for detecting acyclovir, the mol ratio of acyclovir to condensing agent is 1:1.
Further, in the preparation method of the control for detecting acyclovir, the base is one of triethylamine and N, N-diisopropylethylamine.
Further, in the preparation method of the control for detecting acyclovir, the condensing agent is diiodomethane.
Further, in the preparation method of the control for detecting acyclovir, the solvent is one of dimethyl sulfoxide, N-dimethylformamide, acetonitrile and tetrahydrofuran.
Further, in the preparation method of the control for detecting acyclovir, the developing agent for column purification used in the process of column purification is DCM: CH 3 Oh=1:1 (volume ratio).
Compared with the prior art, the technical scheme provided by the invention has the following technical advantages:
1. according to the technical scheme provided by the invention, acyclovir is used as a raw material, and a reference substance for detecting acyclovir is generated under the action of diiodomethane and alkali; the material is used as an impurity in acyclovir detection, and has great promotion effects on the research of acyclovir related quality, the improvement of the medication safety, reliability and stability of related preparations and the quality control in the production process of bulk drugs and preparations.
2. The preparation method for detecting acyclovir reference substance provided by the invention has the advantages that the synthetic route is simple, the reaction condition is mild, the raw materials and the reagent are cheap and easy to obtain, and for the preparation liquid phase separation technology adopted by the preparation of general impurities, more target products can be directly obtained by the method, under the condition that the current impurity market price is high and is difficult to buy, a relatively convenient and reliable obtaining channel is provided for the research of acyclovir impurity, and the cost is greatly reduced.
Drawings
Fig. 1 is an HPLC diagram of a control provided in example 6 for detecting acyclovir.
Fig. 2 is a mass spectrum of a control for detecting acyclovir provided in example 6.
Fig. 3 is a HNMR diagram of a control for detecting acyclovir provided in example 6.
Fig. 4 is a CNMR diagram of a control for detecting acyclovir provided in example 6.
Detailed Description
The following description of the technical solution of the present invention will be clear and complete, and it is obvious that the described embodiments are only main test procedures of the present invention, and may be performed with reference to conventional techniques for process parameters or conditions that are not specifically noted.
Example 1
Acyclovir (2.25 g), ACN (acetonitrile) 50ml, TEA (triethylamine) 0.7g, CH were added to a 100ml single port flask 2 I 2 (diiodomethane) 1.335g, heated to 30℃for 16h, and purified by silica gel column (DCM: CH) 3 Oh=1:1) to give a white solid, purity by HPLC: 98.2%.
Example 2
Acyclovir (2.25 g), DMSO (dimethyl sulfoxide) 50ml, TEA 0.7g, CH were added to a 100ml single-necked flask 2 I 2 1.335g, heated to 90℃for 8h, and purified by column chromatography on silica gel (DCM: CH 3 Oh=1:1) to give a white solid, purity by HPLC: 97.5%.
Example 3
Acyclovir (2.25 g), ACN (acetonitrile) 50ml, TEA (triethylamine) 1.1g, CH were added to a 100ml single-necked flask 2 I 2 (diiodomethane) 5.5g, heated to 10deg.C for 12h, and purified on silica gel column (DCM: CH) 3 Oh=1:1) to give a white solid, purity by HPLC: 92.5%.
Example 4
Acyclovir (2.25 g), ACN (acetonitrile) 50ml, TEA (triethylamine) 3g, CH were added to a 100ml single-necked flask 2 I 2 (diiodomethane) 0.55g, heated to 100deg.C for 10h, and purified by silica gel column (DCM: CH) 3 Oh=1:1) to give a white solid, purity by HPLC: 97.9%.
Example 5
Acyclovir (2.25 g), ACN (acetonitrile) 50ml, TEA (triethylamine) 2g, CH were added to a 100ml single-necked flask 2 I 2 (diiodomethane) 2.2g, addThe reaction was heated to 50℃for 15h, and the reaction was completed and purified by silica gel column (DCM: CH 3 Oh=1:1) to give a white solid, purity by HPLC: 98.8%.
Example 6
Acyclovir 2.25g, DMF (N, N-dimethylformamide) 50ml, DIEA (N, N-diisopropylethylamine) 0.7g, CH were added to a 100ml single-port flask 2 I 2 (diiodomethane) 1.335g, heated to 80℃for 16h, and purified by silica gel column (DCM: CH) 3 Oh=1:1) to give a white solid, purity by HPLC: 99.08%.
MS, HNMR, CNMR and HPLC detection profiles are shown in figures 1 to 4; the analysis is as follows:
fig. 1 is a graph showing the results of HPLC detection of a control for acyclovir detection prepared in this example.
Fig. 2 is a mass spectrometry analysis: MS results [ m+1] =463, [2m+1] =925, consistent with target product molecular weight 462.
Fig. 3 is HNMR analysis: 1 H-NMR(500MHz，DMSO-d 6 ): delta 7.94 (s, 2H), delta 7.81 (s, 4H), delta 6.30 (s, 2H), delta 5.35 (s, 4H), delta 4.60-4.62 (t, 2H), delta 3.45-3.48 (m, 8H), consistent with the target product structure.
Fig. 4 is CNMR analysis: 13 C-NMR(500MHz，DMSO-d 6 ) Delta 157.30, delta 152.92, delta 151.08, delta 138.54, delta 117.43, delta 72.49, delta 71.19, delta 60.40, delta 48.20, consistent with the target product structure.
Claims (4)
1. The preparation method of the reference substance for detecting acyclovir is characterized by comprising the following steps in sequence:
dissolving acyclovir in an organic solvent, reacting for 8-16 hours at 10-100 ℃ under the action of condensing agent and alkali to obtain a reaction solution containing a reference substance for detecting acyclovir, and finally purifying by a column to obtain the reference substance of acyclovir, wherein the structural formula of the reference substance is shown in formula 1;
the mol ratio of the acyclovir to the alkali is as follows: 1:0.5-3;
the mol ratio of the acyclovir to the condensing agent is as follows: 1:0.2-2;
the alkali is one of triethylamine and N, N-diisopropylethylamine;
the condensing agent is diiodomethane;
the developing agent for column purification used in the column purification process is DCM: CH 3 OH=1:1；
The control of acyclovir has the structural formula:
；
formula 1.
2. The method for preparing a control for detecting acyclovir according to claim 1, wherein the molar ratio of acyclovir to alkali is: 1:1.5.
3. The method for preparing a control for detecting acyclovir according to claim 1, wherein the molar ratio of acyclovir to condensing agent is: 1:1.
4. The method for preparing a control for detecting acyclovir according to claim 1, wherein the solvent is one of dimethyl sulfoxide, N-dimethylformamide, acetonitrile and tetrahydrofuran.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5654286A (en) * | 1993-05-12 | 1997-08-05 | Hostetler; Karl Y. | Nucleotides for topical treatment of psoriasis, and methods for using same |
| US5879700A (en) * | 1991-10-15 | 1999-03-09 | Hostetler; Karl Y. | Nucleoside analogue phosphates for topical use |
| CN1221609A (en) * | 1995-06-07 | 1999-07-07 | 卡尔Y·霍斯泰特勒 | Use of adenosine phosphates in preparation of medicaments and phamacentical formulations |
| WO2020036545A1 (en) * | 2018-08-17 | 2020-02-20 | İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Phase stable topical composition comprising acyclovir and hydrocortisone |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014008197A1 (en) * | 2012-07-03 | 2014-01-09 | 3-V Biosciences, Inc. | Heterocyclic modulators of lipid synthesis |
| US10226449B2 (en) * | 2013-12-20 | 2019-03-12 | 3-V Biosciences, Inc. | Heterocyclic modulators of lipid synthesis and combinations thereof |
| CN110831600B (en) * | 2017-04-21 | 2023-10-17 | 医肯纳肿瘤学公司 | Indole AHR inhibitors and uses thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5879700A (en) * | 1991-10-15 | 1999-03-09 | Hostetler; Karl Y. | Nucleoside analogue phosphates for topical use |
| US5654286A (en) * | 1993-05-12 | 1997-08-05 | Hostetler; Karl Y. | Nucleotides for topical treatment of psoriasis, and methods for using same |
| CN1221609A (en) * | 1995-06-07 | 1999-07-07 | 卡尔Y·霍斯泰特勒 | Use of adenosine phosphates in preparation of medicaments and phamacentical formulations |
| WO2020036545A1 (en) * | 2018-08-17 | 2020-02-20 | İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Phase stable topical composition comprising acyclovir and hydrocortisone |
Non-Patent Citations (5)
| Title |
|---|
| Assessment of the surface energy of powders by contact angle measurement and inverse gas chromatography;O Planinsek et al;《Farmacevtski Vestnik》;全文 * |
| Benzimidazole nucleosides： antiviral and antitumour activities and methods of synthesis;Maria I. Kharitonova et al;《Russian Chemical Reviews》;全文 * |
| 克力托辛(Clitocine)及其类似物的合成与生物活性;郭翔海;康宏;郑岚曦;姜申德;;有机化学;20110215(02);全文 * |
| 环境介质中典型新型有机污染物分析技术研究进展;朱帅 等;《岩矿测试》;全文 * |
| 阿昔洛韦有关物质的合成;周文高;《精细与专用化学品》;全文 * |
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