CN101863808B - New preparation method for important fenticonazole nitrate intermediate - Google Patents
New preparation method for important fenticonazole nitrate intermediate Download PDFInfo
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- CN101863808B CN101863808B CN200910082255.6A CN200910082255A CN101863808B CN 101863808 B CN101863808 B CN 101863808B CN 200910082255 A CN200910082255 A CN 200910082255A CN 101863808 B CN101863808 B CN 101863808B
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- fenticonazole nitrate
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- 229960001337 fenticonazole nitrate Drugs 0.000 title abstract description 11
- FJNRUWDGCVDXLU-UHFFFAOYSA-N fenticonazole nitrate Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 FJNRUWDGCVDXLU-UHFFFAOYSA-N 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 230000000977 initiatory effect Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- -1 N-halogenated succinimide imide Chemical class 0.000 claims description 5
- 238000005286 illumination Methods 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000003568 thioethers Chemical class 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract description 3
- RBDDRTHNIQZYPD-UHFFFAOYSA-N 2-[4-(chloromethyl)phenyl]thiophene Chemical compound C1=CC(CCl)=CC=C1C1=CC=CS1 RBDDRTHNIQZYPD-UHFFFAOYSA-N 0.000 abstract description 2
- ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical group C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 abstract 1
- 230000000843 anti-fungal effect Effects 0.000 abstract 1
- 229940121375 antifungal agent Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method for a compound in a formula (I), namely 4-thiophenyl benzyl chloride, which comprises the following step of: converting p-methyl diphenyl sulfide (a compound in a formula II) and N-halogenated succinimide (a compound in a formula III) into the compound in the formula (I) under the initiation of an alkane reagent and free radicals, wherein the compound in the formula (I) is an important intermediate for preparing fenticonazole nitrate (a compound in a formula IV). The fenticonazole nitrate is an excellent antifungal medicament. The formulas (I), (II), (III) and (IV) are shown in the description.
Description
Technical field
The present invention relates to a kind of preparation method of new important fenticonazole nitrate intermediate, a kind of good antifungal drug of fenticonazole nitrate, is mainly used in the treatment of women's gynecopathy.
Background technology
A kind of good antifungal drug of fenticonazole nitrate, is mainly used in the treatment of women's gynecopathy, has of great value pharmacological properties.Therefore develop fenticonazole nitrate and will bring good economic benefit and social benefit, its chemical structural formula is shown below:
Shown in formula (IV), compound is fenticonazole nitrate, reports and be shown below its synthetic method in patent US4221803 and DE2917244:
Wherein, about the preparation of 4-thiophenyl benzyl chloride, patent US3242193 provides a similar synthetic method, is shown below:
Pharmacy value based on fenticonazole nitrate and good market outlook, use for reference aforesaid method, we use cheap raw material to methyldiphenyl thioether and N-halogenated succinimide imide, develop a kind of method of preparing 4-thiophenyl halogen benzyl that good yield and controllability are strong, will be significant for synthesis type (I) compound.
Summary of the invention
The object of this invention is to provide the preparation method of the important fenticonazole nitrate intermediate that a kind of yield is good, controllability is strong.
This patent provides the preparation method of compound shown in formula (I).Comprise the following steps:
A) methyldiphenyl thioether (formula II compound) and N-halogenated succinimide imide (formula III compound) are converted into formula (I) compound under the effect of alkane reagent and free radical initiation;
B) after completion of the reaction, reaction solution after filtration, washing, concentrated, the dry crude product that obtains formula (I) compound;
C) crude product of formula (I) compound obtains formula I pure compounds through underpressure distillation;
1. method according to claim 1, is characterized in that the X in formula (III) compound is halogen, preferably Cl and Br, more preferably Br.
2. method according to claim 1, is characterized in that the preferred chloroform of alkane solvent and tetracol phenixin, the more preferably tetracol phenixin that in reaction, use.
3. method according to claim 1, is characterized in that the mode that free radical causes causes for adding initiator azo-bis-isobutyl cyanide, Benzoyl Peroxide, Potassium Persulfate or employing illumination, and more preferably illumination causes.
4. method according to claim 1, the mol ratio that it is characterized in that reacting Chinese style (II) compound and formula (III) compound is 1: 1.0～1: 1.2, preferably 1: 1.0
5. method according to claim 1, is characterized in that the temperature of reaction that formula (II) compound transforms to formula (I) compound is 40～80 ℃, preferably 70～80 ℃.
6. method according to claim 1, is characterized in that the reaction times that formula (II) compound transforms to formula (I) compound is 10～20 hours, preferably 12～16 hours.
Feature of the present invention is, the yield of reaction is higher, and controllability is strong, and the purity of product is high and cost is lower.
Embodiment
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Synthesizing of embodiment 1:4-thiophenyl bromobenzyl
In the dry there-necked flask of 10L, add 5L CCl
4, then add 4-methyldiphenyl thioether 1000g and NBS reagent 934g, and start heated and stirred, carry out mercury lamp simultaneously and irradiate 75～78 ℃ of illumination reaction 12h.Reaction is finished, and is cooled to room temperature, and suction filtration is except insoluble solids, and filtrate is first with 5 L10% sodium bisulfites washings, then washs with 5 L5% sodium hydroxide, finally uses twice of 5L water washing to neutrality.100g anhydrous sodium sulfate drying 0.5h, is spin-dried for solvent, obtains brown oil, and oil pump underpressure distillation crude product is collected 172～180 ℃ of cuts (vacuum tightness is 1mmHg) 1152g, yield 83%.
Synthesizing of embodiment 2:4-thiophenyl benzyl chloride
In the dry there-necked flask of 10L, add 5L CCl
4, then add 4-methyldiphenyl thioether 1000g and NCS reagent 701g, and start heated and stirred, carry out mercury lamp simultaneously and irradiate 75～78 ℃ of illumination reaction 16h.Reaction is finished, and is cooled to room temperature, and suction filtration is except insoluble solids, and filtrate is first with 5 L10% sodium bisulfites washings, then washs with 5 L5% sodium hydroxide, finally uses twice of 5L water washing to neutrality.100g anhydrous sodium sulfate drying 0.5h, is spin-dried for solvent, obtains 1322g brown oil, and oil pump underpressure distillation crude product is collected 152～160 ℃ of cuts (vacuum tightness is 1mmHg) 1008g, yield 86.4%.
Claims (2)
1. a method of preparing 4-thiophenyl halogen benzyl (formula I compound), is characterized by:
A) methyldiphenyl thioether (formula II compound) and N-halogenated succinimide imide (formula III compound) are converted into formula (I) compound under tetracol phenixin and illumination initiation; The mol ratio of described reaction Chinese style (II) compound and formula (III) compound is 1:1.0; The temperature of reaction that described formula (II) compound transforms to formula (I) compound is 70～80 ℃, and the reaction times is 12～16 hours;
B) after completion of the reaction, reaction solution after filtration, washing, concentrated, the dry crude product that obtains formula (I) compound;
C) crude product of formula (I) compound obtains formula I pure compounds through underpressure distillation;
2. method according to claim 1, is characterized in that the X in formula (III) compound is Cl, Br.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910082255.6A CN101863808B (en) | 2009-04-20 | 2009-04-20 | New preparation method for important fenticonazole nitrate intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910082255.6A CN101863808B (en) | 2009-04-20 | 2009-04-20 | New preparation method for important fenticonazole nitrate intermediate |
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| Publication Number | Publication Date |
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| CN101863808A CN101863808A (en) | 2010-10-20 |
| CN101863808B true CN101863808B (en) | 2014-05-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910082255.6A Active CN101863808B (en) | 2009-04-20 | 2009-04-20 | New preparation method for important fenticonazole nitrate intermediate |
Country Status (1)
| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3242193A (en) * | 1961-03-13 | 1966-03-22 | Merck & Co Inc | Indolyl aliphatic acids |
| CN101195575A (en) * | 2006-12-08 | 2008-06-11 | 西北师范大学 | process for producing (E)-3-dimethoxy-4'-acetoxy diphenyl ethylene |
-
2009
- 2009-04-20 CN CN200910082255.6A patent/CN101863808B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3242193A (en) * | 1961-03-13 | 1966-03-22 | Merck & Co Inc | Indolyl aliphatic acids |
| CN101195575A (en) * | 2006-12-08 | 2008-06-11 | 西北师范大学 | process for producing (E)-3-dimethoxy-4'-acetoxy diphenyl ethylene |
Non-Patent Citations (3)
| Title |
|---|
| 李丽娟，叶昌伦.卤取代反应.《药物合成反应技术与方法》.化学工业出版社,2005, * |
| 相转移催化法合成硝酸芬替康唑;陈宝泉;《中国药物化学杂志》;20070228;第17卷(第1期);第52-53页 * |
| 陈宝泉.相转移催化法合成硝酸芬替康唑.《中国药物化学杂志》.2007,第17卷(第1期), |
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| CN101863808A (en) | 2010-10-20 |
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Effective date of registration: 20201202 Address after: No. 279 Nanhai Road, Xiuying District 570314 Hainan city of Haikou Province Patentee after: AVENTIS PHARMA (HAINAN) Co.,Ltd. Address before: 100097, Wanquan mansion, 3 Jin Zhuang, Haidian District, Beijing, Sijiqing Patentee before: BEIJING D-VENTUREPHARM TECHNOLOGY DEVELOPMENT Co.,Ltd. |
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Addressee: Song Xuemei Document name: Notice of conformity |
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Denomination of invention: A New Preparation Method for Important Intermediate of Nitrofenticonazole Nitrate Granted publication date: 20140507 Pledgee: Sanya Rural Commercial Bank Co.,Ltd. Pledgor: AVENTIS PHARMA (HAINAN) Co.,Ltd. Registration number: Y2024980014810 |
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