CN103387537A - Preparation method of compound requalinium chloride - Google Patents
Preparation method of compound requalinium chloride Download PDFInfo
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- CN103387537A CN103387537A CN2013103131715A CN201310313171A CN103387537A CN 103387537 A CN103387537 A CN 103387537A CN 2013103131715 A CN2013103131715 A CN 2013103131715A CN 201310313171 A CN201310313171 A CN 201310313171A CN 103387537 A CN103387537 A CN 103387537A
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Abstract
The invention belongs to the field of pharmaceutical synthesis, relates to a preparation method of an antibacterial drug and in particular relates to a preparation method of a compound requalinium chloride. The preparation method has the main characteristics that highly toxic nitrobenzene used in the prior art is abolished, but non-toxic isoamyl alcohol is used as a reaction solvent to prepare requalinium chloride, so that the purity is higher than that of the method using nitrobenzene, and the yield is equal to that of the prior art using nitrobenzene. According to the preparation method of the compound requalinium chloride, the isoamyl alcohol is used as the solvent, so that a problem that the nitrobenzene is harmful to the human body while being used as the solvent can be solved.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to a kind of preparation method of antibacterials, be specifically related to a kind of preparation method of compound Dequavet.
Background technology
Dequavet is cats product, has broad-spectrum antibacterial action, and is effective to common malignant bacteria and the fungi infestation of oral cavity and bottleneck throat, is used for acute and chronic pharyngolaryngitis, stomatocace, gingivitis.
Oral cavity and Throat diseases, be common disease, frequently-occurring disease, and Dequavet obtains wide clinical application always.
The synthetic of Dequavet is all by 4-amidoquinaldine, 1, and 10-diiodo-decane is starting raw material, and reaction obtains through 2 steps, and reaction can be expressed as follows:
4-amidoquinaldine decane 1, two (the 4-amidoquinaldine iodo) salt of 10-
Dequalinium chloride
The preparation method of existing published Dequavet, in the first step reaction, use the oil of mirbane of severe toxicity as reaction solvent, and is " research of Synthetic Technique of Dequaliniuni Chloride " (Hebei chemical industry the 4th phase in 2000), to its preparation method, very detailed publicly.
Oil of mirbane (being commonly called as the artificial almond oil) is a kind of hypertoxic organism, sucks steam or skin and is infected with in a large number, can cause acute poisoning, minimum lethal dose; People's per os 200mg/kg.
Therefore, oil of mirbane, as the synthetic reaction solvent of medicine, should be avoided, unless can prove in medicine and there is no the oil of mirbane residue fully, but this is very inaccessible, therefore, how in Dequavet synthetic, getting rid of oil of mirbane, is the problem that we should consider.
Summary of the invention
Purpose of the present invention is exactly in order to improve the synthesis technique of Dequavet, do not use oil of mirbane, but, 4-amidoquinaldine, 1, the reaction of 10-diiodo-decane is very harsh to the use of solvent, the one, 4-amidoquinaldine, 1, and the steric hindrance of 10-diiodo-decane condensation reaction is large, the solvent of selecting must help to overcome the reaction steric hindrance, in the 2nd, 4-amidoquinaldine molecule-NH
2Group also can react with 1,10-diiodo-decane, and produces side reaction, and the solvent of selecting must help to reduce side reaction and occur.
The inventor is surprised to find that: primary isoamyl alcohol, as reaction solvent,, in suitable temperature of reaction, under the condition of proportioning raw materials, can make 4-amidoquinaldine, 1, and the condensation reaction of 10-diiodo-decane is carried out smoothly, simultaneously, has reduced the generation of side reaction.Its purity is higher than using oil of mirbane, and its yield and oil of mirbane are substantially suitable as reaction solvent, see embodiment 1～4.
Primary isoamyl alcohol is a kind of substantially nontoxic solvent, and apple brandy fragrance and sharp flavor are arranged.China GB2760-86 is defined as and allows the flavouring agent that uses, mainly in order to prepare apple and Banana Type essence.Therefore, the present invention uses primary isoamyl alcohol as solvent, can solve oil of mirbane as the harmful problem of solvent.
The inventor has invented the preparation method of compound Dequavet, and the method comprises the steps
:
(1) in reaction vessel, add 4-amidoquinaldine, 1,10-diiodo-decane, then add solvent, and be heated to 130～140 ℃, reacted 24 hours, finish reaction.Be cooled to room temperature, crystallization.Filter, filter cake is only used washing with alcohol, and 60～65 ℃ of dryings, obtain the lark crystallization, is decane 1, two (the 4-amidoquinaldine iodo) salt of 10-.
(2) in reaction vessel, add decane 1, two (the 4-amidoquinaldine iodo) salt of 10-, add methyl alcohol, logical hydrogen chloride gas, be heated to reflux, and back flow reaction 3.5～4 hours, finish reaction, is cooled to room temperature, crystallization.Filter, filter cake is only with the alcohol washing, and 60～65 ℃ of dryings, obtain the lark crystallization, is the dequalinium chloride crude product.Crude product is dissolved in boiling water, is cooled to room temperature, crystallization obtains dequalinium chloride.
In above-mentioned preparation method, the preferred primary isoamyl alcohol of solvent in (1).
Inventor's discovery, material proportion is: the 4-amidoquinaldine: 1,10-diiodo-decane=2～2.6: 1 mol/mol; The 4-amidoquinaldine: primary isoamyl alcohol=1: 3～5 W/V, be conducive to the carrying out that reacts, wherein, preferred; 4-amidoquinaldine: 1,10-diiodo-decane=2.4～2.5: 1 mol/mol; 4-amidoquinaldine: primary isoamyl alcohol=1: 4 W/V.
The inventor also finds: in former technique, washing leaching cake technique is numerous and diverse, as described in " research of Synthetic Technique of Dequaliniuni Chloride ": in the reaction of (1) step, filter cake needs oil of mirbane, acetone, dilute hydrochloric acid, water washing, and in the reaction of (2) step, filter cake needs dilute hydrochloric acid, water washing.The present invention only uses ethanol to wash filter cake, has reached the identical effect of former washing, simultaneously, has reduced the impact on environment of oil of mirbane in former washing, acetone, dilute hydrochloric acid.
Embodiment
Following embodiment is used for further narration the present invention.
Embodiment 1:Decane 1, the preparation method 1 (solvent primary isoamyl alcohol) of two (the 4-amidoquinaldine iodo) salt of 10-
In the 10L there-necked flask, add 4-amidoquinaldine 870g (5.480mol), 1,10-diiodo-decane 864g (2.192mol), then add primary isoamyl alcohol 3480ml, and be heated to 133 ℃, reacted 24 hours, finish reaction.Be cooled to room temperature, crystallization.Filter, filter cake 1000ml washing with alcohol, 60～65 ℃ of dryings, obtain lark crystallization 910 grams (pure), is decane 1, two (the 4-amidoquinaldine iodo) salt of 10-.Yield 45.2%.High performance liquid chromatography detects, purity 81.2%.
Embodiment 2:Decane 1, the preparation method 2 (solvent primary isoamyl alcohol) of two (the 4-amidoquinaldine iodo) salt of 10-
In the 10L there-necked flask, add 4-amidoquinaldine 835g (5.261mol), 1,10-diiodo-decane 864g (2.192mol), then add primary isoamyl alcohol 3340ml, and be heated to 133 ℃, reacted 24 hours, finish reaction.Be cooled to room temperature, crystallization.Filter, filter cake 1000ml washing with alcohol, 60～65 ℃ of dryings, obtain lark crystallization 930 grams (pure), is decane 1, two (the 4-amidoquinaldine iodo) salt of 10-.Yield 46.2%.High performance liquid chromatography detects, purity 81.9%.
Embodiment 3:Decane 1, the preparation method 3 (solvent primary isoamyl alcohol) of two (the 4-amidoquinaldine iodo) salt of 10-
In the 10L there-necked flask, add 4-amidoquinaldine 695g (4.384mol), 1,10-diiodo-decane 864g (2.192mol), then add primary isoamyl alcohol 3475ml, and be heated to 133 ℃, reacted 24 hours, finish reaction.Be cooled to room temperature, crystallization.Filter, filter cake 1000ml washing with alcohol, 60～65 ℃ of dryings, obtain lark crystallization 880 grams (pure), is decane 1, two (the 4-amidoquinaldine iodo) salt of 10-.Yield 43.7%.High performance liquid chromatography detects, purity 80.1%.
Embodiment 4:Contrast experiment: decane 1, the preparation method 4 (solvent oil of mirbane) of two (the 4-amidoquinaldine iodo) salt of 10-
, according to " research of Synthetic Technique of Dequaliniuni Chloride " disclosed method,, as solvent, prepare decane 1 with oil of mirbane, two (the 4-amidoquinaldine iodo) salt of 10-:
In the 10L there-necked flask, add 4-amidoquinaldine 1270g, 1,10-diiodo-decane 864g, then add oil of mirbane primary isoamyl alcohol 2667ml, and be heated to 150～160 ℃, reacted 6 hours, finish reaction.Be cooled to room temperature, crystallization.Filter, filter cake is with using respectively 300ml oil of mirbane, 300ml acetone, 300ml dilute hydrochloric acid, 500ml water washing, and 60～65 ℃ of dryings, obtain lark crystallization 900 grams (pure), is decane 1, two (the 4-amidoquinaldine iodo) salt of 10-.Yield 45.2%.High performance liquid chromatography detects, purity 78.1%.
Embodiment 5:The preparation of dequalinium chloride
In the 10L there-necked flask, add decane 1, two (4-amidoquinaldine iodo) the salt 900g of 10-, add methyl alcohol 3600ml, logical hydrogen chloride gas, be heated to reflux, and back flow reaction 3.5～4 hours, finish reaction.Filter, filter cake 1000ml washing with alcohol, 60～65 ℃ of dryings, obtain the lark crystallization, is dequalinium chloride crude product 550g.
Crude product is dissolved in 15L boiling water, is cooled to room temperature, crystallization obtains dequalinium chloride 400g.Content 98.1%.
The detection method that relates to embodiment
1. decane 1, the detection method of two (the 4-amidoquinaldine iodo) purity salts of 10-:
Detect with high performance liquid chromatography:
Stationary phase: octadecyl silane.Moving phase: methyl alcohol, water mixed liquid, methyl alcohol: water=7: 3 V/V.
2. dequalinium chloride detection method of content: get this product 0.200 gram, add the 5ml anhydrous methanol and dissolve, add the 50ml acetic anhydride, 0.1mol perchloric acid titration drop is fixed.
Claims (6)
1. the preparation method of a compound Dequavet, the method comprises the steps
:
(1) in reaction vessel, add 4-amidoquinaldine, 1,10-diiodo-decane, then add solvent, and be heated to 130～140 ℃, reacted 24 hours, finish reaction; Be cooled to room temperature, crystallization; Filter, filter cake is only with the alcohol washing, and 60～65 ℃ of dryings, obtain the lark crystallization, is decane 1, two (the 4-amidoquinaldine iodo) salt of 10-;
(2) in reaction vessel, add decane 1, two (the 4-amidoquinaldine iodo) salt of 10-, add methyl alcohol, logical hydrogen chloride gas, be heated to reflux, and back flow reaction 3.5～4 hours, finish reaction, is cooled to room temperature, crystallization; Filter, filter cake is only with the alcohol washing, and 60～65 ℃ of dryings, obtain the lark crystallization, is the dequalinium chloride crude product; Crude product is dissolved in boiling water, is cooled to room temperature, crystallization obtains dequalinium chloride.
2. method according to claim 1, is characterized in that: the preferred primary isoamyl alcohol of solvent in (1).
According to claim 1 to 2 described method, it is characterized in that: the 4-amidoquinaldine: 1,10-diiodo-decane=2～2.6: 1 mol/mol.
4. method according to claim 3, is characterized in that: the 4-amidoquinaldine: 1,10-diiodo-decane=2.4～2.5: 1 mol/mol.
According to claim 1 to 2 described method, it is characterized in that: the 4-amidoquinaldine: primary isoamyl alcohol=1: 3～5 W/V.
6. preparation method according to claim 1, is characterized in that: wash the filter cake preferred alcohol with alcohol described in (1), (2).
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103749457A (en) * | 2013-12-27 | 2014-04-30 | 上海市计划生育科学研究所 | Application of dequalinium chloride as mouse birth control medicine |
| CN105859615A (en) * | 2016-05-11 | 2016-08-17 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method and novel intermediate of dequalinium chloride |
| CN106632031A (en) * | 2016-12-13 | 2017-05-10 | 珠海同源药业有限公司 | Dequalinium chloride crystal and buccal tablet thereof, and preparation method of buccal tablet |
| CN106632032A (en) * | 2016-12-26 | 2017-05-10 | 华润双鹤药业股份有限公司 | Dequalinium and preparation method thereof |
| CN106854179A (en) * | 2016-12-26 | 2017-06-16 | 华润双鹤药业股份有限公司 | The preparation method of Dequalinium Chloride and the like |
| CN107827814A (en) * | 2017-11-24 | 2018-03-23 | 安徽恒星制药有限公司 | A kind of Dequalinium Chloride crystal formation A preparation method |
| CN107941960A (en) * | 2017-12-27 | 2018-04-20 | 宁波季诺化学品有限公司 | A kind of HPLC analytical method of 4 amidoquinaldine |
| CN108570005A (en) * | 2017-03-08 | 2018-09-25 | 刘力 | Dequalinium Chloride noval chemical compound and combinations thereof and purposes |
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| US20070025942A1 (en) * | 2005-07-26 | 2007-02-01 | Joshi Vijay K | Clear gel antiperspirant or deodorant compositions and related methods |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103749457A (en) * | 2013-12-27 | 2014-04-30 | 上海市计划生育科学研究所 | Application of dequalinium chloride as mouse birth control medicine |
| CN105859615A (en) * | 2016-05-11 | 2016-08-17 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method and novel intermediate of dequalinium chloride |
| CN105859615B (en) * | 2016-05-11 | 2019-05-03 | 安徽恒星制药有限公司 | A kind of preparation method and intermediate of Dequalinium Chloride |
| CN106632031A (en) * | 2016-12-13 | 2017-05-10 | 珠海同源药业有限公司 | Dequalinium chloride crystal and buccal tablet thereof, and preparation method of buccal tablet |
| CN106632032A (en) * | 2016-12-26 | 2017-05-10 | 华润双鹤药业股份有限公司 | Dequalinium and preparation method thereof |
| CN106854179A (en) * | 2016-12-26 | 2017-06-16 | 华润双鹤药业股份有限公司 | The preparation method of Dequalinium Chloride and the like |
| CN106632032B (en) * | 2016-12-26 | 2019-08-06 | 华润双鹤药业股份有限公司 | Dequalinium Chloride and preparation method thereof |
| CN106854179B (en) * | 2016-12-26 | 2019-12-06 | 华润双鹤药业股份有限公司 | Preparation method of dequalinium chloride and analogs thereof |
| CN108570005A (en) * | 2017-03-08 | 2018-09-25 | 刘力 | Dequalinium Chloride noval chemical compound and combinations thereof and purposes |
| CN107827814A (en) * | 2017-11-24 | 2018-03-23 | 安徽恒星制药有限公司 | A kind of Dequalinium Chloride crystal formation A preparation method |
| CN107941960A (en) * | 2017-12-27 | 2018-04-20 | 宁波季诺化学品有限公司 | A kind of HPLC analytical method of 4 amidoquinaldine |
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Address after: 519041 Guangdong province Zhuhai Sanzao Jinhai Road No. 6 Patentee after: Zhuhai homologous Pharmaceutical Co., Ltd. Address before: 519041 Guangdong province Zhuhai Sanzao Jinhai Road No. 6 Patentee before: Biochemical Pharmaceutical Factory of Zhuhai S.E.Z. |