CN102295623B - Method for preparing N-acetylmorpholine by using ketene - Google Patents
Method for preparing N-acetylmorpholine by using ketene Download PDFInfo
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- CN102295623B CN102295623B CN2011101388063A CN201110138806A CN102295623B CN 102295623 B CN102295623 B CN 102295623B CN 2011101388063 A CN2011101388063 A CN 2011101388063A CN 201110138806 A CN201110138806 A CN 201110138806A CN 102295623 B CN102295623 B CN 102295623B
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- ketene
- morpholine
- acetylmorpholine
- acetyl morphine
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/584—Recycling of catalysts
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to a new method for preparing N-acetylmorpholine by using ketene. The technical scheme of the method is that: the method comprises the following synthesis and refining process that: (1) ketene and morpholine are adopted as raw materials, in the presence of an acylating catalyst and an organic solvent, the ketene and the morpholine are subjected to an acylation reaction to obtain a N-acetylmorpholine solution; (2) the N-acetylmorpholine solution is subjected to solvent recovery and reuse, and rectification to prepare the N-acetylmorpholine product. According to the present invention, the yield of the prepared N-acetylmorpholine is up to 98% (calculated as the morpholine), the purity is 99.5%, no waste acid and no waste water are generated, and no environment pollution is generated.
Description
Technical field
The present invention relates to a kind of production method of chemical intermediate N-acetyl morphine.
Background technology
The N-acetyl morphine is important medicine, pesticide intermediate, is the main raw material of synthetic disinfectant use in agriculture enamine morpholine, flumorph.The mixture of N-acetyl morphine and N-N-formyl morpholine N-is good Sweet natural gas and the agent of synthetic gas acid gas removal, is used for the external Morphysorb novel process of exploitation in recent years.
The synthesis technique of N-acetyl morphine mainly contains Acetic (Fr1580614), acetyl chloride method (GB2223492), acetic ester, acetic anhydride method (CN1403449) route.
Acetic conversion rate of products and yield are low, are up to 85% in morpholine, and seriously corroded, production cost is high, quality product is low.
It is acylating agent that the Acetyl Chloride 98Min. route adopts Acetyl Chloride 98Min., and reaction generates the N-acetyl morphine at lower temperature, and yield can reach more than 95%.But Acetyl Chloride 98Min. is expensive, and building-up process produces hydrogenchloride, and seriously corroded needs to adopt pyridine or triethylamine as solvent and de-acidying agent, and the three wastes are more, and solvent recuperation is complicated, and production cost is high.
The acetic ester route adopts acetic ester as acylating agent, must be under strong alkali catalyst exists could with the morpholine effect, have the problem of selecting suitable catalyzer, simultaneously, this reaction is also a reversible reaction, how shifting as soon as possible by product is also an individual difficult problem.
Acetic anhydride method is owing to having passed through acylation process twice, and the transformation efficiency of morpholine has surpassed 98%, and quality product is also high than the Acetyl Chloride 98Min. route.But this method raw material availability too low (utilization ratio of aceticanhydride is only 50%), the production intensity of reactor is little, and production cost is too high.
Summary of the invention
In view of restriction and the shortcoming of above method, need a kind of Innovative method of exploitation, the method should be able to be avoided the intrinsic shortcoming of currently known methods.The present invention has developed a kind of N-of preparation acetyl morphine yield up to 98% (in morpholine), and purity reaches 99.5%, also produces the synthetic method of environmentally safe without spent acid and waste water.
Purpose of the present invention is achieved through the following technical solutions:
A kind of ketene prepares the method for N-acetyl morphine, under acylation catalyst exists, morpholine and ketene in organic solvent in 5～30 ℃ of reactions 3～8 hours, preparation N-acetyl morphine crude product, then pass through solvent recuperation and apply mechanically with rectifying and prepare N-acetyl morphine product.
Reaction equation is as follows:
With respect to Acetic, Acetyl Chloride 98Min. route, acetic ester route, acetic anhydride method, method of the present invention does not have the generation of by product, and product separation is relatively simple, and there is no the generation of spent acid waste liquid.
Preferably, described acylation catalyst is selected from triethylamine, 4, one or more in DMAP, triethylene diamine, Tetramethyl Ethylene Diamine etc.; The mass ratio of acylation catalyst and morpholine is (0.001～0.009): 1.
The acylation catalyst that the present invention uses has improved reaction efficiency greatly.Not only the reaction times is starkly lower than literature value, and due to the interaction of acylation catalyst and ketene, makes temperature of reaction obviously reduce.And in experiment, the discovery that we are taken aback, the present invention use ketene as reactant, can be in lower temperature (5～30 ℃) reaction, and conventional patents is when using ketene as reactant, temperature of reaction is generally at 140～150 ℃.In reaction process of the present invention, equipment running cost is low, and is little to the corrodibility of equipment.
Preferably, described morpholine and ketene mass ratio are (2.07～2.17): 1.
Preferably, described organic solvent is selected from one or more in methylene dichloride, ethylene dichloride, chloroform, ethyl acetate etc.; Organic solvent and morpholine mass ratio are (1～2): 1; The solvent recuperation of using is directly applied mechanically.Described organic solvent reclaims (comprise and heat up in a steamer head) and directly applies mechanically, and the organic solvent in reaction is directly used in the production of next batch product, does not need purification processes.Generally in industrial production, organic solvent will be purified and can reuse through classification, but in the method for the invention, the discovery that we are taken aback, solvent can directly be applied mechanically, and applies mechanically purity and the productive rate impact of product very little.This makes in industrial production and solvent directly can be applied mechanically, and does not need to add solvent recuperation or equipment for purifying, facility investment and the running cost of greatly saving; And realized that Green Chemistry is synthetic, reached without discharging of waste liquid.
Preferably, described temperature of reaction is 15～30 ℃.
Preferably, the described reaction times is 3～6 hours.
With respect to prior art, the present invention has the following advantages and beneficial effect:
1. raw materials cost is lower, is fit to serialization production;
2. temperature of reaction is lower, is fit to suitability for industrialized production;
3. production process does not produce hydrogenchloride or acetic acid, corrosion is less, and three waste discharge is few;
4. directly apply mechanically after solvent returns, realized that greenization is synthetic, product yield reaches 98.0%, and purity reaches 99.5%.
Embodiment
With the following Examples the present invention is further detailed, but the scope of protection of present invention is not limited to the present invention the scope that represents in embodiment in order better to explain.
Embodiment 1
In the four-hole boiling flask that electric stirring, logical ketene gas pipe, thermometer and vapor pipe are housed, add 300g morpholine, 1.5 gram triethylamines, 450g methylene dichloride, open and stir, passed into ketene 143g within 4 hours at 20 ℃.After normal pressure reclaimed solvent, rectifying was carried out in decompression, under-0.099Mpa, collected 100～103 ℃ of cuts, obtained purity and be 99.5% N-acetyl morphine 291.2g (98.2%).
The impact that the recovery solvent is applied mechanically product yield and purity sees the following form:
| Apply mechanically number of times | Productive rate (%) | Purity (%) |
| 1 | 98.0 | 99.5 |
| 2 | 98.3 | 99.4 |
| 3 | 98.2 | 99.4 |
| 4 | 98.0 | 99.6 |
| 5 | 98.2 | 99.5 |
| 6 | 98.1 | 99.4 |
Embodiment 2
In the four-hole boiling flask that electric stirring, logical ketene gas pipe, thermometer and vapor pipe are housed, add 200g morpholine, 1.0 gram triethylamines, 300g methylene dichloride, open and stir, passed into ketene 94.5g within 4 hours at 25 ℃.After normal pressure reclaimed solvent, rectifying was carried out in decompression, under-0.099Mpa, collected 100～103 ℃ of cuts, obtained purity and be 99.4% N-acetyl morphine 436g (98.0%).。
Embodiment 3
In the four-hole boiling flask that electric stirring, logical ketene gas pipe, thermometer and vapor pipe are housed, add 300g morpholine, 1.0 gram triethylamines, 470g methylene dichloride, open and stir, passed into ketene 144g within 4 hours at 25 ℃.After normal pressure reclaimed solvent, rectifying was carried out in decompression, under-0.099Mpa, collected 100～103 ℃ of cuts, obtained purity and be 99.6% N-acetyl morphine 434.6g (97.8%).
Embodiment 4
In the four-hole boiling flask that electric stirring, logical ketene gas pipe, thermometer and vapor pipe are housed, add 300g morpholine, 1.7 gram triethylamines, 450g methylene dichloride, open and stir, passed into ketene 145g within 4 hours at 25 ℃.After normal pressure reclaimed solvent, rectifying was carried out in decompression, under-0.099Mpa, collected 100～103 ℃ of cuts, obtained purity and be 99.4% N-acetyl morphine 437.6g (98.4%).
Embodiment 5
In the four-hole boiling flask that electric stirring, logical ketene gas pipe, thermometer and vapor pipe are housed, add 300g morpholine, 0.3 gram 4, DMAP, 600g chloroform are opened and are stirred, and pass into ketene 144g within 6 hours at 15 ℃.After normal pressure reclaimed solvent, rectifying was carried out in decompression, under-0.099Mpa, collected 100～103 ℃ of cuts, obtained purity and be 99.6% N-acetyl morphine 437.6g (98.4%).
Embodiment 6
In the four-hole boiling flask that electric stirring, logical ketene gas pipe, thermometer and vapor pipe are housed, add 300g morpholine, 22 gram triethylene diamines, 300g ethyl acetate, open and stir, passed into ketene 146g within 8 hours at 5 ℃.After normal pressure reclaimed solvent, rectifying was carried out in decompression, under-0.099Mpa, collected 100～103 ℃ of cuts, obtained purity and be 99.2% N-acetyl morphine 438.6g (98.6%).
Claims (5)
1. a ketene prepares the method for N-acetyl morphine, it is characterized in that, under acylation catalyst exists, morpholine and ketene in organic solvent 5～30 ℃ reacted 3～8 hours, preparation N-acetyl morphine crude product, then apply mechanically with rectifying through solvent recuperation and prepare N-acetyl morphine product; Described acylation catalyst is selected from triethylamine, 4, DMAP or triethylene diamine; The mass ratio of acylation catalyst and morpholine is 0.001～0.009: 1.
2. ketene according to claim 1 prepares the method for N-acetyl morphine, it is characterized in that described morpholine and ketene mass ratio are (2.07～2.17): 1.
3. ketene according to claim 1 and 2 prepares the method for N-acetyl morphine, it is characterized in that described organic solvent is selected from one or more in methylene dichloride, ethylene dichloride, chloroform or ethyl acetate; Organic solvent and morpholine mass ratio are (1～2): 1; Directly apply mechanically after the solvent recuperation of using.
4. ketene according to claim 1 and 2 prepares the method for N-acetyl morphine, it is characterized in that described temperature of reaction is 15～30 ℃.
5. ketene according to claim 1 and 2 prepares the method for N-acetyl morphine, it is characterized in that the described reaction times is 3～6 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101388063A CN102295623B (en) | 2011-05-26 | 2011-05-26 | Method for preparing N-acetylmorpholine by using ketene |
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| CN102295623A CN102295623A (en) | 2011-12-28 |
| CN102295623B true CN102295623B (en) | 2013-05-22 |
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| CN103641797B (en) * | 2013-09-11 | 2015-07-08 | 西南化工研究设计院有限公司 | Preparation method for N-acetyl morpholine |
| CN103524457A (en) * | 2013-09-13 | 2014-01-22 | 江苏集贤绿色化学科技研究院有限公司 | Synthetic method of medicinal intermediate acetylpiperidine |
| CN103664838B (en) * | 2013-12-16 | 2015-10-21 | 山东汇海医药化工有限公司 | A kind of ketene prepares the method for 2-acetofuran |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3755318A (en) * | 1971-04-05 | 1973-08-28 | Wacker Chemie Gmbh | Process for producing primary carboxylic acid amides |
| CN1403449A (en) * | 2001-09-13 | 2003-03-19 | 沈阳化工研究院 | Prepn of acetyl morphine |
| CN1721415A (en) * | 2004-07-16 | 2006-01-18 | 中国石油天然气集团公司 | Process for preparing N-acetyl morpholine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3755318A (en) * | 1971-04-05 | 1973-08-28 | Wacker Chemie Gmbh | Process for producing primary carboxylic acid amides |
| CN1403449A (en) * | 2001-09-13 | 2003-03-19 | 沈阳化工研究院 | Prepn of acetyl morphine |
| CN1721415A (en) * | 2004-07-16 | 2006-01-18 | 中国石油天然气集团公司 | Process for preparing N-acetyl morpholine |
Non-Patent Citations (2)
| Title |
|---|
| N_乙酰吗啉合成工艺的研究进展;刘瑞江等;《化工进展》;20091231;第28卷(第10期);1828-1832,1841 * |
| 刘瑞江等.N_乙酰吗啉合成工艺的研究进展.《化工进展》.2009,第28卷(第10期),1828-1832,1841. |
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Denomination of invention: A method for preparing n-acetylmorpholine from vinyl ketone Effective date of registration: 20211130 Granted publication date: 20130522 Pledgee: Dongying Hekou District sub branch of China Post Savings Bank Co.,Ltd. Pledgor: SHANDONG HUIHAI PHARMACEUTICAL& CHEMICAL Co.,Ltd. Registration number: Y2021980013568 |
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