CN105294729A - Method for eliminating by-product dimethyl sulfide during Moxidectin production process - Google Patents
Method for eliminating by-product dimethyl sulfide during Moxidectin production process Download PDFInfo
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- CN105294729A CN105294729A CN201510766597.5A CN201510766597A CN105294729A CN 105294729 A CN105294729 A CN 105294729A CN 201510766597 A CN201510766597 A CN 201510766597A CN 105294729 A CN105294729 A CN 105294729A
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
The invention discloses a method for eliminating a by-product dimethyl sulfide during a Moxidectin production process, which belongs to the technical field of chemical production. During the Moxidectin production process, after an oxidation reaction step is complete, excessive aqueous hydrogen peroxide solution is added in an oxidation reaction solution and a mixture is fully stirred, the by-product dimethyl sulfide content in the oxidation reaction solution can be rapidly reduced to less than 0.1% in 0.5-3.0 hours, and thereby, the operation environment for subsequent steps can be improved. The method has the advantages of short period, low cost of raw material, simple process, and no extra equipment requirement.
Description
Technical field
The present invention relates to chemical production technical field, be specifically related to the removing method of by product dimethyl thioether in a kind of mosictin production process.
Background technology
Mosictin is a kind of semisynthetic Macrocyclolactone lactone kind medicine, there is good anthelmintic activity, there is the characteristics such as long-acting, safe simultaneously, a kind of wide spectrum, efficient, Novel macrocyclic lactone expelling parasite microbiotic (Parasites & Vectors2009 of being widely used in veterinary clinic at present, 2 (Suppl2), S5).At present, producing the main path of mosictin is take nimoctin as raw material, successively through upper protection, oxidation, oximate and go protection four step chemical reaction step to obtain (CN104017001; AU2006203459; US4988824), concrete chemical reaction process is shown in Fig. 1.
In the process of above-mentioned production mosictin, oxidation step uses in a lot of operational path " activation dimethyl sulfoxide (DMSO) reagent " (Synthesis, 1990,857-870; Synthesis, 1981,165-185) as oxidation system, such as, system (US4988824,1991 such as dimethyl sulfoxide (DMSO)/dichloro-phenyl phosphate, dimethyl sulfoxide (DMSO)/sulfur trioxide pyridine, dimethyl sulfoxide (DMSO)/Vanadium Pentoxide in FLAKES; CN1051043,1991), these systems are nonmetal oxidation system, avoid metal residual and pollute the shortcoming of the finished product, but the by product dimethyl thioether that oxidising process produces has that boiling point is low, volatile, inflammable, stench, have the features such as pungency (conventional Hazardous Chemical Substances security manual, the first roll to nose larynx, first version, China Medical Science Press, 1992), have a strong impact on oxidation and subsequent step production operation environment.Therefore, the elimination technique that research mosictin production technique oxidizing reaction process procedure generates by product dimethyl thioether is necessary very much, is also the inherent requirement of environment protection standard.
Chinese patent 201410522597.6(denomination of invention: a kind of method eliminating by product dimethyl thioether in mosictin production process) in disclose a kind of aqueous sodium hypochlorite solution that uses as absorption reagent, adopt the mode advertising gas precipitation or negative pressure precipitation to be transferred in clorox absorption kettle together with condenser by the by product dimethyl thioether produced in oxidation step and solvent for use, reclaim reaction solvent by the chlorine bleach liquor's oxidative absorption dimethyl thioether in clorox absorption kettle.The weak point of this processing method is to need additionally increase absorption unit, condensing equipment and vacuum system or consume a large amount of gas.
Summary of the invention
In order to overcome in existing mosictin production technique the weak point eliminated by product dimethyl thioether and exist, the object of the present invention is to provide the removing method of by product dimethyl thioether in a kind of mosictin production process, the method utilizes aqueous hydrogen peroxide solution for by product dimethyl thioether in oxygenant elimination mosictin production process, without the need to additionally increasing absorption and condensing equipment, there is cycle short, the advantage such as raw materials cost is low, absorption technique is simple.
For achieving the above object, the technical solution used in the present invention is:
The removing method of by product dimethyl thioether in a kind of mosictin production process, the method is taking nimoctin as raw material, successively through upper protection, oxidation, oximate and go protection four step chemical reaction step produce mosictin process in, after oxidation step terminates, excessive aqueous hydrogen peroxide solution is added in oxidation liquid, under agitation condition, the dimethyl sulphide ether content contained in oxidation liquid is down to less than 0.1%, and then carries out oximate and protective reaction process; Wherein, after oxidation step terminates, add in the process of excessive aqueous hydrogen peroxide solution and follow-up stirring in gained oxidation liquid, oxidizing reaction liquid temp controls at 10 ~ 50 DEG C, and churning time is 0.5-3.0 hour; Described oxidizing reaction uses activation dimethyl sulfoxide (DMSO) reagent as oxidation system.
Described oxidation step detailed process is: obtain the nimoctin protected with 4-chlorobenzene oxygen ethanoyl after described nimoctin raw material and 4-chlorophenoxy excess acetyl chloride; by raw for solvent for use hybrid concurrency in itself and described activation dimethyl sulfoxide (DMSO) reagent and oxidation step oxidizing reaction; generate by product dimethyl thioether simultaneously; oxidation products obtains mosictin product for oximation reaction and protective reaction successively, yield and quality product unaffected.
In described oxidation step, solvent for use is methylene dichloride, 1,2-ethylene dichloride or chloroform.
Described activation dimethyl sulfoxide (DMSO) reagent oxidation system is dimethyl sulfoxide (DMSO)/dichloro-phenyl phosphate, dimethyl sulfoxide (DMSO)/sulfur trioxide pyridine or dimethyl sulfoxide (DMSO)/Vanadium Pentoxide in FLAKES.
In described aqueous hydrogen peroxide solution, concentration of hydrogen peroxide scope is 5 ~ 50wt.%
Described aqueous hydrogen peroxide solution add-on is 1.0 ~ 20.0 times of calculating that oxidizing reaction produces theoretical dimethyl thioether mole number according to hydrogen peroxide mole number contained by it.
The principle of the invention is as follows:
In this project oxidizing process, aqueous hydrogen peroxide solution can Quick Oxidation dimethyl thioether, generate odorless, high boiling dimethyl sulfoxide (DMSO), and can directly add in oxidation liquid, while cancellation oxidizing reaction, also play the effect eliminating dimethyl thioether.Therefore, take aqueous hydrogen peroxide solution as oxygenant, the dimethyl thioether that in elimination mosictin production technique, oxidizing reaction process procedure generates can reach the object of rapid Optimum production environment, decreasing pollution on the basis not increasing extras.
Invention beneficial effect
1, the inventive method is in mosictin production technique, use " activation dimethyl sulfoxide (DMSO) reagent " make to add in the oxidation liquid of oxidation system the aqueous hydrogen peroxide solution of by product dimethyl thioether 1.0-20.0 times amount and fully stir 0.5-3.0 hour, the dimethyl sulphide ether content contained can be down to less than 0.1% fast in oxidizing reaction.
2, the inventive method having that the cycle is short, raw materials cost is low, absorption technique is simple, absorbing and the advantage such as condensation or gas apparatus without the need to increasing.
Accompanying drawing explanation
Fig. 1 is mosictin synthetic route chart.
Embodiment
Below in conjunction with drawings and Examples, the invention will be further described.
In following examples, mosictin production process is all be raw material with nimoctin, successively through upper protection, oxidation, oximate and go protection four step chemical reaction step to generate mosictin; Described oxidizing reaction is specially: obtain the nimoctin protected with 4-chlorobenzene oxygen ethanoyl after described nimoctin raw material and 4-chlorobenzene oxygen excess acetyl chloride; Then carry out oxidation step, be about to the raw oxidizing reaction of solvent for use hybrid concurrency in nimoctin, activation dimethyl sulfoxide (DMSO) reagent and the oxidation step protected with 4-chlorophenoxy ethanoyl, generate by product dimethyl thioether simultaneously.After above-mentioned oxidizing reaction, add excessive aqueous hydrogen peroxide solution at gained oxidation liquid (comprising oxidation products and by product dimethyl thioether), after stirring for some time, be down to less than 0.1% fast by the dimethyl sulphide ether content contained in oxidation liquid; Oxidation liquid after above-mentioned process obtains mosictin product for oximation reaction and protective reaction more successively, yield and quality product unaffected.
Embodiment 1
Nimoctin is dissolved in reaction solvent methylene dichloride, add acid binding agent triethylamine and upper protection reagent 4-chlorophenoxy Acetyl Chloride 98Min. subsequently, be stirred well to reaction to terminate, add excessive shrend to go out reaction solution, divide oil-yielding stratum, the nimoctin with blocking group is obtained through super-dry precipitation, by itself and activation dimethyl sulfoxide (DMSO) reagent (dimethyl sulfoxide (DMSO)/dichloro-phenyl phosphate), oxidizing reaction is carried out in triethylamine and methylene dichloride mixing, after reaching reaction end, add the theoretical 5.0wt.% aqueous hydrogen peroxide solution producing dimethyl thioether 4.0 times amount, vigorous stirring 3.0h, oxidizing reaction liquid temp controls at 25-30 DEG C, after stratification, take off layer oxidation liquid and detect residue dimethyl sulphide ether content for vapor-phase chromatography.
Embodiment 2
Nimoctin is dissolved in reaction solvent methylene dichloride, add acid binding agent triethylamine and upper protection reagent 4-chlorophenoxy Acetyl Chloride 98Min. subsequently, be stirred well to reaction to terminate, add excessive shrend to go out reaction solution, divide oil-yielding stratum, the nimoctin with blocking group is obtained through super-dry precipitation, by itself and activation dimethyl sulfoxide (DMSO) reagent (dimethyl sulfoxide (DMSO)/dichloro-phenyl phosphate), oxidizing reaction is carried out in triethylamine and methylene dichloride mixing, after reaching reaction end, add the theoretical 10.0wt.% aqueous hydrogen peroxide solution producing dimethyl thioether 9.0 times amount, vigorous stirring 1.5h, oxidizing reaction liquid temp controls at 20-30 DEG C, after stratification, take off layer oxidation liquid and detect residue dimethyl sulphide ether content for vapor-phase chromatography.
Embodiment 3
Nimoctin is dissolved in reaction solvent methylene dichloride, add acid binding agent triethylamine and upper protection reagent 4-chlorophenoxy Acetyl Chloride 98Min. subsequently, be stirred well to reaction to terminate, add excessive shrend to go out reaction solution, divide oil-yielding stratum, the nimoctin with blocking group is obtained through super-dry precipitation, by itself and activation dimethyl sulfoxide (DMSO) reagent (dimethyl sulfoxide (DMSO)/dichloro-phenyl phosphate), oxidizing reaction is carried out in triethylamine and methylene dichloride mixing, after reaching reaction end, add the theoretical 10.0wt.% aqueous hydrogen peroxide solution producing dimethyl thioether 9.0 times amount, vigorous stirring 1.0h, oxidizing reaction liquid temp controls at 33-35 DEG C, after stratification, take off layer oxidation liquid and detect residue dimethyl sulphide ether content for vapor-phase chromatography.
Embodiment 4
Nimoctin is dissolved in reaction solvent methylene dichloride, add acid binding agent triethylamine and upper protection reagent 4-chlorophenoxy Acetyl Chloride 98Min. subsequently, be stirred well to reaction to terminate, add excessive shrend to go out reaction solution, divide oil-yielding stratum, the nimoctin with blocking group is obtained through super-dry precipitation, by itself and activation dimethyl sulfoxide (DMSO) reagent (dimethyl sulfoxide (DMSO)/dichloro-phenyl phosphate), oxidizing reaction is carried out in triethylamine and methylene dichloride mixing, after reaching reaction end, add the theoretical 15.0wt.% aqueous hydrogen peroxide solution producing dimethyl thioether 18.0 times amount, vigorous stirring 0.5h, oxidizing reaction liquid temp controls at 30-35 DEG C, after stratification, take off layer oxidation liquid and detect residue dimethyl sulphide ether content for vapor-phase chromatography.
Embodiment 5
Nimoctin is dissolved in reaction solvent methylene dichloride, add acid binding agent triethylamine and upper protection reagent 4-chlorophenoxy Acetyl Chloride 98Min. subsequently, be stirred well to reaction to terminate, add excessive shrend to go out reaction solution, divide oil-yielding stratum, the nimoctin with blocking group is obtained through super-dry precipitation, it is mixed with activation dimethyl sulfoxide (DMSO) reagent (dimethyl sulfoxide (DMSO)/Vanadium Pentoxide in FLAKES) and methylene dichloride and carries out oxidizing reaction, after reaching reaction end, first acid binding agent triethylamine is added, add the theoretical 10.0wt.% aqueous hydrogen peroxide solution producing dimethyl thioether 9.0 times amount again, vigorous stirring 1.0h, oxidizing reaction liquid temp controls at 20-30 DEG C, after stratification, take off layer oxidation liquid and detect residue dimethyl sulphide ether content for vapor-phase chromatography.
The parameter that above-described embodiment 1-5 implementation process relates to and experimental result as shown in table 1.
Each parameter and experimental result in table 1 embodiment 1-5
Remarks:
adMS-dimethyl thioether;
bthe amount of theoretical multiple-add hydrogen peroxide material is the multiple that oxidizing reaction theory generates DMS amount.
Claims (10)
1. the removing method of by product dimethyl thioether in a mosictin production process, it is characterized in that: the method is taking nimoctin as raw material, successively through upper protection, oxidation, oximate and go protection four step chemical reaction step produce mosictin process in, after oxidation step terminates, excessive aqueous hydrogen peroxide solution is added in oxidation liquid, stir, and then carry out oximate and protective reaction process; Described oxidizing reaction uses activation dimethyl sulfoxide (DMSO) reagent as oxidation system.
2. the removing method of by product dimethyl thioether in mosictin production process according to claim 1; it is characterized in that: described oxidation step detailed process is: after described nimoctin raw material and 4-chlorobenzene oxygen excess acetyl chloride, obtain the nimoctin protected with 4-chlorobenzene oxygen ethanoyl; then there is oxidizing reaction; generate by product dimethyl thioether simultaneously; oxidation products obtains mosictin product for oximation reaction and protective reaction successively, yield and quality product unaffected.
3. the removing method of by product dimethyl thioether in mosictin production process according to claim 2, is characterized in that: in described oxidation step, solvent for use is methylene dichloride, 1,2-ethylene dichloride or chloroform.
4. the method for by product dimethyl thioether in elimination mosictin production process according to claim 1 and 2, is characterized in that: described activation dimethyl sulfoxide (DMSO) reagent oxidation system is dimethyl sulfoxide (DMSO)/dichloro-phenyl phosphate, dimethyl sulfoxide (DMSO)/sulfur trioxide pyridine or dimethyl sulfoxide (DMSO)/Vanadium Pentoxide in FLAKES.
5. the removing method of by product dimethyl thioether in mosictin production process according to claim 1, it is characterized in that: after oxidation step terminates, add in gained oxidation liquid in the process of excessive aqueous hydrogen peroxide solution and follow-up stirring, oxidizing reaction liquid temp controls at 10 ~ 50 DEG C, and churning time is 0.5-3.0 hour.
6. the removing method of by product dimethyl thioether in mosictin production process according to claim 1, is characterized in that: in described aqueous hydrogen peroxide solution, concentration of hydrogen peroxide scope is 5 ~ 50wt.%.
7. the removing method of by product dimethyl thioether in the mosictin production process according to claim 1 or 6, is characterized in that: described aqueous hydrogen peroxide solution add-on is 1.0 ~ 20.0 times of calculating that oxidizing reaction produces theoretical dimethyl thioether mole number according to hydrogen peroxide mole number contained by it.
8. the removing method of by product dimethyl thioether in mosictin production process according to claim 7, is characterized in that: add aqueous hydrogen peroxide solution and after stirring, the dimethyl sulphide ether content contained in reaction solution is down to less than 0.1%.
9. the removing method of by product dimethyl thioether in mosictin production process according to claim 7, is characterized in that: add aqueous hydrogen peroxide solution and after stirring, the dimethyl sulphide ether content contained in reaction solution is down to less than 0.05%.
10. the removing method of by product dimethyl thioether in mosictin production process according to claim 7, is characterized in that: add aqueous hydrogen peroxide solution and after stirring, the dimethyl sulphide ether content contained in reaction solution is down to less than 0.02%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601735A (en) * | 2013-11-08 | 2014-02-26 | 大连九信生物化工科技有限公司 | Method for purifying moxidectin |
| CN104017001A (en) * | 2014-06-18 | 2014-09-03 | 大连九信生物化工科技有限公司 | Method of chemically synthesizing moxidectin |
| CN104292239A (en) * | 2014-09-30 | 2015-01-21 | 大连九信生物化工科技有限公司 | Method for removing by-product dimethyl sulfide in moxidectin production process |
| CN104370781A (en) * | 2014-10-31 | 2015-02-25 | 瓮福（集团）有限责任公司 | Method for removing sodium nitrite out of waste dimethyl sulfoxide salt by using composite oxidizing agent |
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2015
- 2015-11-12 CN CN201510766597.5A patent/CN105294729A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601735A (en) * | 2013-11-08 | 2014-02-26 | 大连九信生物化工科技有限公司 | Method for purifying moxidectin |
| CN104017001A (en) * | 2014-06-18 | 2014-09-03 | 大连九信生物化工科技有限公司 | Method of chemically synthesizing moxidectin |
| CN104292239A (en) * | 2014-09-30 | 2015-01-21 | 大连九信生物化工科技有限公司 | Method for removing by-product dimethyl sulfide in moxidectin production process |
| CN104370781A (en) * | 2014-10-31 | 2015-02-25 | 瓮福（集团）有限责任公司 | Method for removing sodium nitrite out of waste dimethyl sulfoxide salt by using composite oxidizing agent |
Non-Patent Citations (3)
| Title |
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| 李敬芬: "《药物合成反应》", 31 August 2010 * |
| 高建敏 等: "神农丹农药恶臭废气资源化治理研究", 《中国环境管理干部学院学报》 * |
| 龚元新: "二甲硫醚废气的综合处理技术", 《宁波化工》 * |
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Effective date of registration: 20170122 Address after: East Road, Wuda Economic Development Zone, Wuhai, the Inner Mongolia Autonomous Region Applicant after: Inner Mongolia RUIMI Fine Chemical Co. Address before: 116600 Dalian economic and Technological Development Zone, Liaoning D double D Double Street, No. 18, No. five Applicant before: Dalian Join King Biological Chemical Technology Co., Ltd. |
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