CN105254560A - Preparation method of decoquinate - Google Patents
Preparation method of decoquinate Download PDFInfo
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- CN105254560A CN105254560A CN201510762509.4A CN201510762509A CN105254560A CN 105254560 A CN105254560 A CN 105254560A CN 201510762509 A CN201510762509 A CN 201510762509A CN 105254560 A CN105254560 A CN 105254560A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a preparation method of decoquinate. Industrialized 2-hydroxyphenylacetic acid phenetole serves as starting materials, and a product with better quality is obtained through diazo coupling, sodium dithionite reduction, condensation, etherificationa and superstrong solid acid SO4<2->/Fe2O3 and sodium bisulfate cyclization. Part intermediate of a synthetic route of the decoquinate does not need to be purified, used solvent is single, aftertreatment of the intermediate and use of organic solvent are reduced, the cost is reduced, the whole process route is short, extremely high temperature or highly corrosive liquid acid is not needed, requirement to equipment is low, operation is easy and convenient, the production cycle is short, produced three wastes are fewer, the production yield is high, the quality is good, and the preparation method of the decoquinate is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation technology of poultry medicine, be specifically related to a kind of preparation method of M and B 15497.
Background technology
The sixties in 20th century M and B 15497 researched and developed by the May & Baker Ltd. (GB) Dageham, Essex RMIO 7XS, England of Britain, and it has wide spectrum coccidiostat activity, can be used for the murder by poisoning of chicken, coccidiosis that tender, huge, heap-type and E.brunetti etc. cause, has wide market outlook.M and B 15497 plays an important role in the DNA building-up process of coccidia, it is stoped to breed mainly through interference DNA synthesis, M and B 15497 toxicity is low, better tolerance, absorb fast, can effective concentration be reached in the short period of time, and metabolism is fast in animal body, residual quantity is low, is widely used in countries such as America and Europes.
In M and B 15497 synthesis technique, ring-closure reaction can carry out under the effect of high boiling solvent or cyclization reagent.CN102816117, CN102766094 adopt high temperature (more than 250 DEG C) cyclization to obtain target product, but because of temperature of reaction high, high to equipment requirements, and carbonization appears in portion of product, is difficult to purifying, yield is low.And with during phosphorus oxychloride cyclization can not one-step synthesis to target product, easily there is material spray in heat accumulation in last handling process, there is larger potential safety hazard.Patent CN101012195 adopts polyphosphoric acid cyclization, has corrodibility, and needs the cancellation reaction when comparatively high temps, and heat release is violent, and the phosphoric acid salt of generation is difficult to and product separation, aftertreatment difficulty.
Summary of the invention
For solving the problem, the invention provides a kind of preparation method of M and B 15497, with industrialized 2-ethoxy-phenol for starting raw material, with water, methyl alcohol, DMF for solvent, the organic solvent rate of recovery is high, the generation three wastes are few, through diazonium coupling, vat powder reduction, condensation, etherificate, superpower solid acid SO
4 2-/ Fe
2o
3close ring with sodium pyrosulfate and obtain the measured product of matter, reduce cost.
For achieving the above object, the technical scheme that the present invention takes is:
A preparation method for M and B 15497, comprises the steps:
S1, in reactor drop into 7.5 parts of aniline, 22 parts of water, be cooled to 0 DEG C, slowly stir, stream adds 30 ~ 32% concentrated hydrochloric acid 21 parts, stream adds complete, and temperature is down to 0 DEG C, and stream adds sodium nitrite solution, after stream adds, continue to react 1h at this temperature, obtain the diazonium salt solution of aniline, low temperature is for subsequent use;
S2, in reactor, add 11.8 parts of 2-ethoxy-phenols, 170 parts of methyl alcohol, regulate pH to 8.5 with sodium hydroxide solution, after stirring at room temperature 1h, be cooled to less than-5 DEG C, stream adds the diazonium salt solution of the aniline of step S1 gained, regulate pH=7 with sodium hydroxide solution, stream adds complete simultaneously, regulates pH=7 ~ 8, be warming up to 8 DEG C, continue stirring reaction 4h, reducing pressure steams recovery by the methyl alcohol in system, obtains 3-oxyethyl group-4-hydroxyazo benzene distillation viscous fluid;
S3, the 3-oxyethyl group-4-hydroxyazo benzene distillation viscous fluid of gained is mixed with 15.8 parts of sodium hydroxide, 70 parts of water after, rapid stirring is warming up to 85 ~ 90 DEG C, take a policy 38 parts, powder in batches, and insulation reaction 4-5h, is cooled to room temperature, pH to 5-7 is regulated with concentrated hydrochloric acid, stir 1h, filter, 50 DEG C of vacuum-drying 6h, after testing, yield 85%;
S4, add 10.5 parts of 3-oxyethyl group-4-hydroxyanilines in a kettle., 11.6 parts of ethoxy methylenes forks diethyl malonate, 45 parts of methyl alcohol, be warming up to 90 ~ 100 DEG C, after reaction 4 ~ 5h, be cooled to 60 DEG C;
S5, add 11.3 parts, salt of wormwood, bromo-decane 15.7 parts, temperature rising reflux 6 ~ 8h, filter, filter cake 10 parts of methanol wash, filtrate decompression distillation, obtains dope;
S6, the dope of gained is added in 6 parts of DMF, stir, add 2 parts of superpower solid acid SO
4 2-/ Fe
2o
3, 0.02 part of sodium pyrosulfate, is heated to 150 DEG C of reaction 4h, filters and remove solid, after concentrated filtrate, add 4 parts of water, 30% sodium hydroxide solution regulates pH=7 ~ 8, suction filtration, obtain M and B 15497 crude product, obtain off-white color crystalline powder after refining, after testing, total recovery is 65%.
Described sodium nitrite solution is made into by 5.9 parts of Sodium Nitrites and 22 parts of water.
Described vat powder is V-Brite B.
Low temperature in step S1 is 0-10 degree
The present invention has following beneficial effect:
The present invention adopts superpower solid acid SO
4 2-/ Fe
2o
3carry out with sodium pyrosulfate the M and B 15497 that ring-closure reaction obtains, superpower solid acid overcomes the shortcoming of liquid acid, have easily be separated with liquid-phase reaction system, not etching apparatus, aftertreatment is simple, environmental pollution is little, selectivity high.Superpower solid acid SO
4 2-/ Fe
2o
3comparatively bibliographical information is high by 10 ~ 15% to make pass ring yield with sodium pyrosulfate as catalyzer, and aftertreatment is simple.Whole operational path is short, does not need very high temperature or deep-etching liquid acid, and low for equipment requirements, easy and simple to handle, with short production cycle, the three wastes of generation are few; Solvent is single and consumption is few, and cost is low, and product yield is high, and quality is good, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the reaction principle figure of the preparation method of a kind of M and B 15497 of the embodiment of the present invention.
Embodiment
In order to make objects and advantages of the present invention clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
As shown in Figure 1, embodiments provide a kind of preparation method of M and B 15497, comprise the steps:
S1, diazotization
7.5 parts of aniline, 22 parts of water are dropped in reactor, be cooled to 0 DEG C, slowly stir, stream adds 30 ~ 32% concentrated hydrochloric acid 21 parts, stream adds complete, temperature is down to 0 DEG C, and stream adds sodium nitrite solution (5.9 parts, 22 parts, water), after stream adds, continue to react 1h at this temperature, obtain the diazonium salt solution of aniline, low temperature is for subsequent use;
S2, coupling
11.8 parts of 2-ethoxy-phenols, 170 parts of methyl alcohol are added in reactor, regulate pH to 8.5 with sodium hydroxide solution, after stirring at room temperature 1h, be cooled to less than-5 DEG C, stream adds the diazonium salt solution of the aniline of step S1 gained, regulate pH=7 with sodium hydroxide solution, stream adds complete simultaneously, regulates pH=7 ~ 8, be warming up to 8 DEG C, continue stirring reaction 4h, reducing pressure steams recovery by the methyl alcohol in system, obtains 3-oxyethyl group-4-hydroxyazo benzene distillation viscous fluid;
S3, reduction
After the 3-oxyethyl group-4-hydroxyazo benzene distillation viscous fluid of gained is mixed with 15.8 parts of sodium hydroxide, 70 parts of water, rapid stirring is warming up to 85 ~ 90 DEG C, take a policy 38 parts, powder in batches, and insulation reaction 4-5h, is cooled to room temperature, pH to 5-7 is regulated with concentrated hydrochloric acid, stir 1h, filter, 50 DEG C of vacuum-drying 6h, after testing, yield 85%;
S4, condensation
Add 10.5 parts of 3-oxyethyl group-4-hydroxyanilines in a kettle., 11.6 parts of ethoxy methylene forks diethyl malonate, 45 parts of methyl alcohol, be warming up to 90 ~ 100 DEG C, after reaction 4 ~ 5h, be cooled to 60 DEG C;
S5, etherificate
Add 11.3 parts, salt of wormwood, bromo-decane 15.7 parts, temperature rising reflux 6 ~ 8h, filter, filter cake 10 parts of methanol wash, filtrate decompression is distilled, and obtains dope;
S6, cyclization
The dope of gained is added in 6 parts of DMF, stir, add 2 parts of superpower solid acid SO
4 2-/ Fe
2o
3, 0.02 part of sodium pyrosulfate, is heated to 150 DEG C of reaction 4h, filters and remove solid, after concentrated filtrate, add 4 parts of water, 30% sodium hydroxide solution regulates pH=7 ~ 8, suction filtration, obtain M and B 15497 crude product, obtain off-white color crystalline powder after refining, after testing, total recovery is 65%.
This concrete enforcement the present invention is compared with the technique of bibliographical information, and ring-closure reaction is with superpower solid acid SO
4 2-/ Fe
2o
3complete at a higher temperature with sodium pyrosulfate, post-reaction treatment is simple, refiningly further obtains qualified product.Whole technique has good security, controllability, and target product yield is high, and quality is good, and total cost is low, is applicable to suitability for industrialized production.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (4)
1. a preparation method for M and B 15497, is characterized in that, comprises the steps:
S1, in reactor drop into 7.5 parts of aniline, 22 parts of water, be cooled to 0 DEG C, slowly stir, stream adds 30 ~ 32% concentrated hydrochloric acid 21 parts, stream adds complete, and temperature is down to 0 DEG C, and stream adds sodium nitrite solution, after stream adds, continue to react 1h at this temperature, obtain the diazonium salt solution of aniline, low temperature is for subsequent use;
S2, in reactor, add 11.8 parts of 2-ethoxy-phenols, 170 parts of methyl alcohol, regulate pH to 8.5 with sodium hydroxide solution, after stirring at room temperature 1h, be cooled to less than-5 DEG C, stream adds the diazonium salt solution of the aniline of step S1 gained, regulate pH=7 with sodium hydroxide solution, stream adds complete simultaneously, regulates pH=7 ~ 8, be warming up to 8 DEG C, continue stirring reaction 4h, reducing pressure steams recovery by the methyl alcohol in system, obtains 3-oxyethyl group-4-hydroxyazo benzene distillation viscous fluid;
S3, the 3-oxyethyl group-4-hydroxyazo benzene distillation viscous fluid of gained is mixed with 15.8 parts of sodium hydroxide, 70 parts of water after, rapid stirring is warming up to 85 ~ 90 DEG C, take a policy 38 parts, powder in batches, and insulation reaction 4-5h, is cooled to room temperature, pH to 5-7 is regulated with concentrated hydrochloric acid, stir 1h, filter, 50 DEG C of vacuum-drying 6h, after testing, yield 85%;
S4, add 10.5 parts of 3-oxyethyl group-4-hydroxyanilines in a kettle., 11.6 parts of ethoxy methylenes forks diethyl malonate, 45 parts of methyl alcohol, be warming up to 90 ~ 100 DEG C, after reaction 4 ~ 5h, be cooled to 60 DEG C;
S5, add 11.3 parts, salt of wormwood, bromo-decane 15.7 parts, temperature rising reflux 6 ~ 8h, filter, filter cake 10 parts of methanol wash, filtrate decompression distillation, obtains dope;
S6, the dope of gained is added in 6 parts of DMF, stir, add 2 parts of superpower solid acid SO
4 2-/ Fe
2o
3, 0.02 part of sodium pyrosulfate, is heated to 150 DEG C of reaction 4h, filters and remove solid, after concentrated filtrate, add 4 parts of water, 30% sodium hydroxide solution regulates pH=7 ~ 8, suction filtration, obtain M and B 15497 crude product, obtain off-white color crystalline powder after refining, after testing, total recovery is 65%.
2. the preparation method of a kind of M and B 15497 according to claim 1, is characterized in that, described sodium nitrite solution is made into by 5.9 parts of Sodium Nitrites and 22 parts of water.
3. the preparation method of a kind of M and B 15497 according to claim 1, is characterized in that, described vat powder is V-Brite B.
4. the preparation method of a kind of M and B 15497 according to claim 1, is characterized in that, the low temperature in step S1 is 0-10 degree.
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|---|---|---|---|
| CN201510762509.4A CN105254560B (en) | 2015-11-04 | 2015-11-04 | A kind of preparation method of deccox |
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| CN201510762509.4A CN105254560B (en) | 2015-11-04 | 2015-11-04 | A kind of preparation method of deccox |
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|---|---|
| CN105254560A true CN105254560A (en) | 2016-01-20 |
| CN105254560B CN105254560B (en) | 2018-06-22 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382855A (en) * | 2017-06-28 | 2017-11-24 | 浙江荣耀生物科技股份有限公司 | A kind of synthetic method of deccox |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1469416A (en) * | 1973-07-03 | 1977-04-06 | Ciba Geigy Ag | Process for the preparation of quinoline derivatives |
| CN101012195A (en) * | 2007-02-15 | 2007-08-08 | 常熟市欧亚吉生物医药研究所 | Method of preparing 4-hydroxy-6-decyloxy-7-ethoxy-3-quinoline carboxylic acid ethyl ester |
| CN102816117A (en) * | 2012-09-04 | 2012-12-12 | 江苏昊华精细化工有限公司 | Synthesis method of decoquinate |
-
2015
- 2015-11-04 CN CN201510762509.4A patent/CN105254560B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1469416A (en) * | 1973-07-03 | 1977-04-06 | Ciba Geigy Ag | Process for the preparation of quinoline derivatives |
| CN101012195A (en) * | 2007-02-15 | 2007-08-08 | 常熟市欧亚吉生物医药研究所 | Method of preparing 4-hydroxy-6-decyloxy-7-ethoxy-3-quinoline carboxylic acid ethyl ester |
| CN102816117A (en) * | 2012-09-04 | 2012-12-12 | 江苏昊华精细化工有限公司 | Synthesis method of decoquinate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382855A (en) * | 2017-06-28 | 2017-11-24 | 浙江荣耀生物科技股份有限公司 | A kind of synthetic method of deccox |
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| CN105254560B (en) | 2018-06-22 |
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Granted publication date: 20180622 Termination date: 20201104 |