CN103387537B - Preparation method of compound requalinium chloride - Google Patents
Preparation method of compound requalinium chloride Download PDFInfo
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- CN103387537B CN103387537B CN201310313171.5A CN201310313171A CN103387537B CN 103387537 B CN103387537 B CN 103387537B CN 201310313171 A CN201310313171 A CN 201310313171A CN 103387537 B CN103387537 B CN 103387537B
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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 pharmaceutical synthesis field, relate to a kind of preparation method of antibacterials, be specifically related to a kind of preparation method of compound requalinium chloride.
Background technology
Dequavet is cats product, has broad-spectrum antibacterial action, to the common causative bacterium of oral cavity and bottleneck throat and fungi infestation effective, for acute and chronic pharyngolaryngitis, stomatocace, gingivitis.
Oral cavity and Throat diseases, be common disease, frequently-occurring disease, Dequavet obtains wide clinical application always.
The synthesis of Dequavet is all be starting raw material by 4-amidoquinaldine, 1,10-diiodo-decane, and be obtained by reacting through 2 steps, reaction can be expressed as follows:
Two (the 4-amidoquinaldine iodo) salt of 4-amidoquinaldine decane 1,10-
Dequalinium chloride
The preparation method of existing published Dequavet, in the first step reaction, uses the oil of mirbane of severe toxicity as reaction solvent, " 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 artificial almond oil) is a kind of hypertoxic organism, and suction steam or skin are infected with in a large number, can cause acute poisoning, minimum lethal dose; People's per os 200mg/kg.
Therefore, using the reaction solvent of oil of mirbane as pharmaceutical synthesis, should avoid, unless can prove do not have oil of mirbane residue completely in medicine, but this is very inaccessible, therefore, how in the synthesis of Dequavet, getting rid of oil of mirbane, is the problem that we should consider.
Summary of the invention
Object of the present invention is exactly the synthesis technique in order to improve 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, one be 4-amidoquinaldine, 1,10-diiodo-decane condensation reaction steric hindrance large, the solvent selected must help to overcome reaction steric hindrance, and two is-NH in 4-amidoquinaldine molecule
2group also can react with 1,10-diiodo-decane, and produces side reaction, and the solvent selected must help to reduce side reaction and occur.
The present 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, 1,10-diiodo-decane condensation reaction carries out smoothly, meanwhile, decrease the generation of side reaction.Its purity higher than using oil of mirbane, its yield and oil of mirbane as reaction solvent substantially quite, see embodiment 1 ~ 4.
Primary isoamyl alcohol is a kind of substantially nontoxic solvent, has apple brandy fragrance and sharp flavor.China GB2760-86 is defined as the flavouring agent allowing to use, 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 present inventor has invented the preparation method of compound requalinium chloride, and the method comprises the steps
:
(1) in reaction vessel, add 4-amidoquinaldine, 1,10-diiodo-decane, then add solvent, be heated to 130 ~ 140 DEG C, react 24 hours, terminate reaction.Be cooled to room temperature, crystallization.Filter, filter cake only uses washing with alcohol, and 60 ~ 65 DEG C of dryings, obtain lark crystallization, is two (the 4-amidoquinaldine iodo) salt of decane 1,10-.
(2) in reaction vessel, add two (the 4-amidoquinaldine iodo) salt of decane 1,10-, add methyl alcohol, logical hydrogen chloride gas, is heated to backflow, back flow reaction 3.5 ~ 4 hours, terminates reaction, is cooled to room temperature, crystallization.Filter, filter cake is only with alcohol washing, and 60 ~ 65 DEG C of dryings, obtain lark crystallization, are 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).
The present inventor finds, material proportion is: 4-amidoquinaldine: 1,10-diiodo-decane=2 ~ 2.6: 1 mol/mol; 4-amidoquinaldine: primary isoamyl alcohol=1: 3 ~ 5 W/V, is conducive to the carrying out reacted, wherein, preferably; 4-amidoquinaldine: 1,10-diiodo-decane=2.4 ~ 2.5: 1 mol/mol; 4-amidoquinaldine: primary isoamyl alcohol=1: 4 W/V.
The present inventor also finds: washing leaching cake cumbersome in former technique, described by " 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, reaches the effect that former washing is identical, meanwhile, decreases oil of mirbane in former washing, acetone, dilute hydrochloric acid to the impact of environment.
Embodiment
Embodiment is used for describing the present invention further below.
embodiment 1:the preparation method 1 (solvent primary isoamyl alcohol) of two (the 4-amidoquinaldine iodo) salt of decane 1,10-
In 10L there-necked flask, add 4-amidoquinaldine 870g (5.480mol), 1,10-diiodo-decane 864g (2.192mol), then add primary isoamyl alcohol 3480ml, be heated to 133 DEG C, react 24 hours, terminate reaction.Be cooled to room temperature, crystallization.Filter, filter cake 1000ml washing with alcohol, 60 ~ 65 DEG C of dryings, obtain lark crystallization 910 grams (pure), are two (the 4-amidoquinaldine iodo) salt of decane 1,10-.Yield 45.2%.High performance liquid chromatography detects, purity 81.2%.
embodiment 2:the preparation method 2 (solvent primary isoamyl alcohol) of two (the 4-amidoquinaldine iodo) salt of decane 1,10-
In 10L there-necked flask, add 4-amidoquinaldine 835g (5.261mol), 1,10-diiodo-decane 864g (2.192mol), then add primary isoamyl alcohol 3340ml, be heated to 133 DEG C, react 24 hours, terminate reaction.Be cooled to room temperature, crystallization.Filter, filter cake 1000ml washing with alcohol, 60 ~ 65 DEG C of dryings, obtain lark crystallization 930 grams (pure), are two (the 4-amidoquinaldine iodo) salt of decane 1,10-.Yield 46.2%.High performance liquid chromatography detects, purity 81.9%.
embodiment 3:the preparation method 3 (solvent primary isoamyl alcohol) of two (the 4-amidoquinaldine iodo) salt of decane 1,10-
In 10L there-necked flask, add 4-amidoquinaldine 695g (4.384mol), 1,10-diiodo-decane 864g (2.192mol), then add primary isoamyl alcohol 3475ml, be heated to 133 DEG C, react 24 hours, terminate reaction.Be cooled to room temperature, crystallization.Filter, filter cake 1000ml washing with alcohol, 60 ~ 65 DEG C of dryings, obtain lark crystallization 880 grams (pure), are two (the 4-amidoquinaldine iodo) salt of decane 1,10-.Yield 43.7%.High performance liquid chromatography detects, purity 80.1%.
embodiment 4:contrast experiment: the preparation method 4 (solvent oil of mirbane) of two (the 4-amidoquinaldine iodo) salt of decane 1,10-
According to " research of Synthetic Technique of Dequaliniuni Chloride " disclosed method, with oil of mirbane as solvent, prepare two (the 4-amidoquinaldine iodo) salt of decane 1,10-:
In 10L there-necked flask, add 4-amidoquinaldine 1270g, 1,10-diiodo-decane 864g, then add oil of mirbane primary isoamyl alcohol 2667ml, be heated to 150 ~ 160 DEG C, react 6 hours, terminate reaction.Be cooled to room temperature, crystallization.Filter, filter cake is with using 300ml oil of mirbane, 300ml acetone, 300ml dilute hydrochloric acid, 500ml water washing respectively, and 60 ~ 65 DEG C of dryings, obtain lark crystallization 900 grams (pure), is two (the 4-amidoquinaldine iodo) salt of decane 1,10-.Yield 45.2%.High performance liquid chromatography detects, purity 78.1%.
embodiment 5:the preparation of dequalinium chloride
In 10L there-necked flask, add two (4-amidoquinaldine iodo) the salt 900g of decane 1,10-, add methyl alcohol 3600ml, logical hydrogen chloride gas, is heated to backflow, back flow reaction 3.5 ~ 4 hours, terminates reaction.Filter, filter cake 1000ml washing with alcohol, 60 ~ 65 DEG C of dryings, obtain lark crystallization, are 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%.
relate to the detection method of embodiment
1. the detection method of two (the 4-amidoquinaldine iodo) purity salt of decane 1,10-:
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 5ml anhydrous methanol and dissolve, add 50ml acetic anhydride, 0.1mol perchloric acid titration drop is fixed.
Claims (5)
1. a preparation method for compound requalinium chloride, the method comprises the steps:
(1) in reaction vessel, add 4-amidoquinaldine, 1,10-diiodo-decane, then add solvent primary isoamyl alcohol, be heated to 130 ~ 140 DEG C, react 24 hours, terminate reaction; Be cooled to room temperature, crystallization; Filter, filter cake is only with alcohol washing, and 60 ~ 65 DEG C of dryings, obtain lark crystallization, is two (the 4-amidoquinaldine iodo) salt of decane 1,10-;
(2) in reaction vessel, add two (the 4-amidoquinaldine iodo) salt of decane 1,10-, add methyl alcohol, logical hydrogen chloride gas, is heated to backflow, back flow reaction 3.5 ~ 4 hours, terminates reaction, is cooled to room temperature, crystallization; Filter, filter cake is only with alcohol washing, and 60 ~ 65 DEG C of dryings, obtain lark crystallization, are 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: 4-amidoquinaldine: 1,10-diiodo-decane=2 ~ 2.6:1mol/mol.
3. method according to claim 2, is characterized in that: 4-amidoquinaldine: 1,10-diiodo-decane=2.4 ~ 2.5:1mol/mol.
4. method according to claim 1, is characterized in that: 4-amidoquinaldine: primary isoamyl alcohol=1:3 ~ 5W/V.
5. preparation method according to claim 1, is characterized in that: with alcohol washing leaching cake preferred alcohol described in step (1), (2).
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103749457B (en) * | 2013-12-27 | 2015-06-10 | 上海市计划生育科学研究所 | Application of dequalinium chloride as mouse birth control medicine |
| 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 |
| 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 |
| CN107827814B (en) * | 2017-11-24 | 2021-04-20 | 安徽恒星制药有限公司 | Preparation method of dequalinium chloride crystal form A |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997048705A1 (en) * | 1996-06-19 | 1997-12-24 | University College London | Potassium channel blockers |
| WO2008149089A1 (en) * | 2007-06-07 | 2008-12-11 | Syntopix Limited | Antimicrobial formulations comprising a combination of a pyridine thiol and a bis-quinolinium salt |
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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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997048705A1 (en) * | 1996-06-19 | 1997-12-24 | University College London | Potassium channel blockers |
| WO2008149089A1 (en) * | 2007-06-07 | 2008-12-11 | Syntopix Limited | Antimicrobial formulations comprising a combination of a pyridine thiol and a bis-quinolinium salt |
Non-Patent Citations (4)
| Title |
|---|
| Chandima Abeywickrama等.Inhibition of protein kinase C by dequalinium analogues:Structure-activity studies on head group variations.《Bioorganic & * |
| Medicinal Chemistry》.2006,第14卷(第23期),第7798页Scheme 1,第7801页6.2.1. * |
| 史美平,郭曙刚.地喹氯铵合成工艺的研究.《河北化工》.2000,(第4期),第25页1.3.3. * |
| 地喹氯铵合成工艺的研究;朱景 等;《中国药师》;20001231;第3卷(第2期);第73页2.3，第74页2.3.2-2.3.3 * |
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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. |