CN1191250C - Process for synthesizing sertaconazole - Google Patents
Process for synthesizing sertaconazole Download PDFInfo
- Publication number
- CN1191250C CN1191250C CNB011275065A CN01127506A CN1191250C CN 1191250 C CN1191250 C CN 1191250C CN B011275065 A CNB011275065 A CN B011275065A CN 01127506 A CN01127506 A CN 01127506A CN 1191250 C CN1191250 C CN 1191250C
- Authority
- CN
- China
- Prior art keywords
- sertaconazole
- synthetic method
- water
- sertaconazole nitrate
- thiophene
- 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.)
- Expired - Fee Related
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- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 title claims description 16
- 229960005429 sertaconazole Drugs 0.000 title claims description 16
- 230000002194 synthesizing effect Effects 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000019441 ethanol Nutrition 0.000 claims abstract description 12
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims abstract description 12
- 238000010189 synthetic method Methods 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 229930192474 thiophene Natural products 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- HAAITRDZHUANGT-UHFFFAOYSA-N 1-[2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 HAAITRDZHUANGT-UHFFFAOYSA-N 0.000 abstract description 6
- 229960004476 sertaconazole nitrate Drugs 0.000 abstract description 6
- 238000003408 phase transfer catalysis Methods 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004458 analytical method Methods 0.000 abstract description 2
- 238000002329 infrared spectrum Methods 0.000 abstract description 2
- 238000001819 mass spectrum Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract 2
- OFKWTWJUANJQNU-UHFFFAOYSA-N 3-(bromomethyl)-7-chloro-1-benzothiophene Chemical compound ClC1=CC=CC2=C1SC=C2CBr OFKWTWJUANJQNU-UHFFFAOYSA-N 0.000 abstract 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229940075968 desenex Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides a phase transfer catalysis synthetic method for sertaconazole nitrate, which can simplify a synthetic route and can reduce preparation cost. The sertaconazole nitrate synthetic method comprises that 1-(2, 4-dichlorophenyl)-2-(1-imidazole) ethyl alcohol and 3-bromomethyl-7-chlorobenzo [b] thiophene are used as raw materials, toluene and water are used as solvents, tetrabutylammonium chloride is used as a catalyst, a phase transfer catalysis reaction is carried out in the presence of sodium hydroxide, and then the sertaconazole nitrate is obtained. The present invention has the advantage of simple operation and is suitable for industrial production. The present invention also has the advantages of no water-free and oxygen-free operation condition, low cost and stable yield. The chemical structure of the sertaconazole nitrate is confirmed through element analysis, infrared spectrum, NMR hydrogen spectrum, NMR carbon spectrum, mass spectrum, etc., and the content of the sertaconazole nitrate is higher than 98.5%.
Description
Technical field
The present invention relates to a kind of synthetic method of sertaconazole, belong to technical field of organic synthesis, be applicable to preparation medicine material or intermediate.
Background technology
Desenex's sertaconazole (SertaconazoleNitrate), molecular formula: C
20H
15Cl
3N
2OSHNO
3Develop by Spain, and apply for a patent, as ES8504779 multinational; EP151477; ES535656, JP60/181086, US5135943 etc.; its synthetic route adopts with 1-(2; the 4-dichlorobenzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also [b] thiophene be raw material, under protection of inert gas, obtain Sertaconazole, refabrication nitrate with the sodium hydride reaction.Reaction formula is as follows:
The weak point of above-mentioned synthetic method is:
1, reaction needed is finished under protection of inert gas;
2, used sodium hydride meet water can the reaction of blasting property, and meet lower alcohols and also intense reaction can take place, the releasing hydrogen gas burning, so reaction must be operated under anhydrous, oxygen free condition, solvent for use is also must drying anhydrous or do not have a lower alcohols material;
3, used HMPA is toxic substance and costs an arm and a leg;
4, reaction is loaded down with trivial details, condition is restive, cost is higher.
Summary of the invention
The object of the present invention is to provide a kind of phase-transfer catalysis synthetic method of sertaconazole,, reduce preparation cost to simplify synthetic route.
Technical scheme of the present invention is achieved in that the synthetic method of this sertaconazole comprises with 1-(2, the 4-dichlorobenzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also [b] thiophene be raw material, with toluene, water is that solvent, tetrabutylammonium chloride are catalyzer, in the presence of sodium hydroxide, carry out phase-transfer-catalyzed reactions, the preparation sertaconazole.
The synthetic method of described sertaconazole, its feature comprises:
1), with the 1-(2 of 0.2mol, the 4-dichlorobenzene)-also [b] thiophene, 12g sodium hydroxide, the 16ml50% tetrabutylammonium chloride aqueous solution are dissolved in 240ml toluene, the 80ml water for 3-brooethyl-7-chlorobenzene of 2-(1-imidazoles) ethanol, 0.2mol, be warming up to 80 ℃, constant temperature stirred 4 hours, cooling;
2), add 80ml water, use the 4L extracted with diethyl ether for several times then, merge organic layer, use anhydrous sodium sulfate drying, filtration;
3), add the 12ml concentrated nitric acid under the stirring at room, separate out solid, filter;
4), use 95% ethyl alcohol recrystallization, drying under reduced pressure, the white solid sertaconazole.
The technical solution used in the present invention, easy and simple to handle, reaction conditions requires not harsh; Stable yield, cost is lower, is suitable for suitability for industrialized production.
Embodiment
Embodiment:
1), with the 1-(2 of 0.2mol, the 4-dichlorobenzene)-also [b] thiophene, 12g sodium hydroxide, the 16ml50% tetrabutylammonium chloride aqueous solution are dissolved in 240ml toluene, the 80ml water for 3-brooethyl-7-chlorobenzene of 2-(1-imidazoles) ethanol, 0.2mol, be warming up to 80 ℃, constant temperature stirred 4 hours, cooling;
2), add 80ml water, use the 4L extracted with diethyl ether for several times then, merge organic layer, use anhydrous sodium sulfate drying, filtration;
3), add the 12ml concentrated nitric acid under the stirring at room, separate out solid, filter;
4), use 95% ethyl alcohol recrystallization, drying under reduced pressure, white solid sertaconazole 59g, yield 59%, mp157-158 ℃.
Reaction of the present invention is as follows:
The present invention compares with the synthetic method of prior art, has following advantage:
1, the present invention utilizes phase-transfer-catalyzed reactions, and is easy and simple to handle, is suitable for suitability for industrialized production;
2, do not need to control anhydrous, oxygen free operation condition, cost is lower, stable yield;
3, by ultimate analysis, infrared spectra, proton nmr spectra, carbon-13 nmr spectra, mass spectrum etc. are confirmed its chemical structure, and content is greater than 98.5%.
Claims (2)
1, a kind of synthetic method of sertaconazole, its feature comprises with 1-(2, the 4-dichlorobenzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also [b] thiophene be raw material, with toluene, water is that solvent, tetrabutylammonium chloride are catalyzer, in the presence of sodium hydroxide, carry out phase-transfer-catalyzed reactions, the Sertaconazole that obtains adds concentrated nitric acid, the preparation sertaconazole.
2, the synthetic method of sertaconazole according to claim 1, its feature comprises:
1), with the 1-(2 of 0.2mol, the 4-dichlorobenzene)-also [b] thiophene, 12g sodium hydroxide, the 16ml50% tetrabutylammonium chloride aqueous solution are dissolved in 240ml toluene, the 80ml water for 3-brooethyl-7-chlorobenzene of 2-(1-imidazoles) ethanol, 0.2mol, be warming up to 80 ℃, constant temperature stirred 4 hours, cooling;
2), add entry, extracted with diethyl ether, merge organic layer, use anhydrous sodium sulfate drying, filtration;
3), add the 12ml concentrated nitric acid under the stirring at room, separate out solid, filter;
4), use 95% ethyl alcohol recrystallization, drying under reduced pressure, the white solid sertaconazole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011275065A CN1191250C (en) | 2001-09-26 | 2001-09-26 | Process for synthesizing sertaconazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011275065A CN1191250C (en) | 2001-09-26 | 2001-09-26 | Process for synthesizing sertaconazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1358719A CN1358719A (en) | 2002-07-17 |
| CN1191250C true CN1191250C (en) | 2005-03-02 |
Family
ID=4667455
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011275065A Expired - Fee Related CN1191250C (en) | 2001-09-26 | 2001-09-26 | Process for synthesizing sertaconazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1191250C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2249992B1 (en) | 2004-09-13 | 2007-03-01 | Ferrer Internacional, S.A. | A PROCEDURE FOR MANUFACTURING ENANTIOMERIC COMPOUNDS OF IMIDAZOL. |
| ES2249991B1 (en) * | 2004-09-13 | 2007-03-01 | Ferrer Internacional, S.A. | PROCEDURE FOR THE MANUFACTURE OF IMIDAZOLIC COMPOUNDS, THEIR SALTS AND THEIR PSEUDOPOLIMORPHES. |
| CN113501815A (en) * | 2021-07-30 | 2021-10-15 | 海南海神同洲制药有限公司 | Preparation method of sertaconazole nitrate crystal form |
| CN113501814A (en) * | 2021-07-30 | 2021-10-15 | 海南海神同洲制药有限公司 | Method for purifying sertaconazole nitrate |
| CN113735843B (en) * | 2021-09-07 | 2023-05-26 | 海南海神同洲制药有限公司 | Preparation method of low-melting-point sertaconazole nitrate |
-
2001
- 2001-09-26 CN CNB011275065A patent/CN1191250C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1358719A (en) | 2002-07-17 |
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| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
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